Cephalosporins

ABSTRACT

A syn isomer in (R) or (S) form or a mixture thereof of a compound of the formula ##STR1## syn isomer, in the (R) or (S) form or in the form of an (R,S) mixture, in the form of an internal salt or their salts with organic or mineral acids, 
     wherein the variables are herein below defined, having antibacterial properties.

PRIOR APPLICATION

This application is a continuation-in-part of U.S. patent applicationSer. No 989,235 filed Dec. 11, 1992, now U.S. Pat. No. 5,455,238.

STATE OF THE ART

Related prior art includes EP application No. 0,266,060 and U.S. Pat.No. 4,486,586 and U.S. Pat. No. 5,075,298.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel compounds offormula I and their non-toxic, pharmaceutically acceptable acid additionsalts and a process and intermediates for their preparation.

It is another object of the invention to provide novel antibacterialcompositions and a novel method of combatting bacterial infections inwarm-blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are the syn isomer in (R) or (S)form or a mixture thereof of a compound of the formula ##STR2## synisomer, in the (R) or (S) form or in the form of an (R,S) mixture, inthe form of an internal salt or their salts with organic or mineralacids wherein R₇ is selected from the group consisting of ##STR3## R'₁is selected from the group consisting of alkyl of 1 to 4 carbon atoms,--CN, carboxy and alkoxy carbonyl of 1 to 4 alkoxy carbon atoms, R₁, R₂,R₃ and R₅ are individually selected from the group consisting ofhydrogen, halogen, hydroxy, alkyl of 1 to 4 carbon atoms optionallysubstituted with at least one member of the group consisting of halogen,alkoxy and alkylthio of 1 to 4 carbon atoms, --NO₂, --CN, --NH₂, mono-and dialkylamino of 1 to 4 carbon atoms, carbamoyl, (alkylamino)carbonyl of 2 to 5 carbon atoms, (dialkylamino) carbonyl of 3 to 9carbon atoms, carboxy, alkoxycarbonyl of 2 to 5 carbon atoms, acyloxy of1 to 8 carbon atoms and ##STR4## Rx and Ry are individually hydrogen oralkyl of 1 to 4 carbon atoms, R₄ is --OH or alkoxy of 1 to 8 carbonatoms, A and A' are individually selected from the group consisting ofhydrogen, an equivalent of an alkali metal or alkaline earth metal,magnesium, ammonium and an organic amine, or one or two of --COOA or--COOA' are --CO₂ ⁻, the wavy line means --CH₂ R₆ can be in the E or Zposition, R₆ in the quaternary ammonium form is selected from the groupconsisting of ##STR5## X is selected from the group consisting of --CH₂--, --NH--, --O-- and --S--; Q, J, Y, T, U, V, W and Z are individually═N-- or --CH═, each of cyclics containing 1 to 5 heteroatoms of which atleast one is ═N-- and optionally substituted by at least one R or R', Rand R' are individually selected from the group consisting of halogen,alkyl and alkoxy of 1 to 4 carbon atoms, halogen, --CN, --COOQ₁, --CONQ₁Q₂, --NQ₁ Q₂, --SO₂ NQ₁ Q₂, --CSNH₂, --NHCOQ₁, --CH═NOH, --CH═N--O--Q₁,--CH₂ CN and --CH₂ --S--Q₁, Q₁ and Q₂ are individually hydrogen or alkylof 1 to 4 carbon atoms, P₁, P₂ and P₃ are individually alkyl of 1 to 4carbon atoms optionally substituted with a substituent of R or R' or P₁and P₂ taken together with the nitrogen to which they are attached forma 5 or 6 ring heterocyclic with the proviso that when R₃ is --OH oralkoxy of 1 to 8 carbon atoms, at least one of R₁, R₂ and R₅ is otherthan hydrogen.

Examples of alkyl and alkoxy of 1 to 4 carbon atoms are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, methoxy,ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec.-butoxy andtert.-butoxy. Examples of alkylthio of 1 to 4 carbon atoms aremethylthio, ethylhio, propylthio, isopropylthio, butylthio,isobutylthio, sec.-butylthio and tert.-butylthio.

Examples of alkylamino of 1 to 4 carbon atoms are methylamino,ethylamino, propylamino, isopropylamino, butylamino, isobutylamino,sec.-butylamino and tert.-butylamino while examples of dialkylamino of 2to 8 carbon atoms are dimethylamino, diethylamino, diproplylamino,diisopropylamino, dibutylamino, diisobutylamino, ethyl methylamino,propyl methylamino, butyl methylamino and propyl ethylamino.

Examples of (alkylamino) carbonyl of 2 to 5 carbon atoms are(methylamino) carbonyl, (ethylamino) carbonyl, (propylamino) carbonyl,(isopropylamino) carbonyl and (butylamino) carbonyl. Examples ofalkoxycarbonyl of 2 to 5 carbon atoms are methoxycarbonyl andethoxycarbonyl. Examples of (dialkylamino) carbonyl or 3 to 9 carbonatoms are (dimethylamino) carbonyl, (diethylamino) carbonyl,(dipropylamino) carbonyl.

Examples of acyloxy of 1 to 8 carbon atoms are acetoxy, propionyloxy andbenzoyloxy while examples of halogen are fluorine, chlorine, bromine oriodine.

When P₁ and P₂ form a heterocycle with the nitrogen atom to which theyare attached, it may be pyrrolidine, morpholine or piperidine. When R₄is alkoxy, it is preferably acetoxy, propionyloxy or benzoyloxy.

Among the values of A' and A are an equivalent of sodium, potassium,lithium, calcium, magnesium or ammonium and organic bases such asmethylamine, propylamine, trimethylamine, diethylamine, triethylamine,N,N-dimethylethanolamine, tris[(hydroxymethyl)-amino]-methane,ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine,benzylamine, procaine, lysine, arginine, histidine andN-methylglucamine.

The products of formula I can also appear in the form of a pure internalsalt, in salified form or in a combined form with the acids of thesolution. Among the acids with which the products of formula I can besalified include acetic acid, trifluoroacetic acid, maleic acid,tartaric acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, phosphoric acid, sulfuric acid, hydrochloricacid, hydrobromic acid, hydroiodic acid.

In the invention, more preferably A' is hydrogen and CO2A is CO₂ ⁻.

The expression in the form of quaternary ammonium indicates that R₆ islinked by one of the nitrogen atoms that it contains. Preferably R₆ isone of the following: ##STR6## Prefered compounds are those wherein:

R₆ is quinolinium, isoquinolinium, 4-(methylthio)-pyridinium,thieno[2,3-b]pyridinium, imidazo(1,2-a)pyridinium or6,7-dihydro-5H-pyrindinium, those in which R₃ and R₄ individually arehydroxy and those in which R₂ and R₅ are chlorine or fluorine, those inwhich R₁ and R₂ are fluorine and those in which R₂ is methoxy and one ofR₁ or R₅ is chlorine and those wherein R'₁ is --CN, --COOH oralkoxycarbonyl.

Specific compounds of the invention are the internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)imidazo (1,2-a) pyridinium,

the internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazoa)pyridinium,

the internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2-chloro-4,5-dihydroxy-3-methoxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)quinolinium,

the internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-6,7-dihydro-5H-pyridininium,

the internal salt of (6R-(3-(E)6α,7β(Z(S*))))-1-(3-(7-(((2-amino-4-thiazoyl)(carboxy-(3,4-dihydroxy-5-fluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-quinolinium,

the internal salt of [6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)[carboxy-(2-chloro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium(R) or (S) or an (R+S) mixture,

the internal salt of [6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)[carboxy-(3-cyano-4,5-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium(R) or (S) or an (R+S) mixture,

the internal salt of [6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)(carboxy-(3-fluoro-4,5-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium(R) or (S) or an (R+S) mixture,

the internal salt of [6R-[3(E),6α,7β(Z)]]-2-[3-[7-[[(2-amino-4-thiazolyl)[carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium(R) or (S) or an (R+S) mixture,

the internal salt of [6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)(carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-thieno[2,3-b]pyridinium(R) or (S) or an (R+S) mixture,

the internal salt of [6R-[3(E),6α,7β[Z(S*)]]]-1-[3-[7-[[(2-amino-4-thiazolyl)[carboxy-(3-cyano-4,5-dihydro-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,20]-oct-2-en-3-yl]-2-propenyl]-thieno[2,3-b]pyridinium,

the internal salt of [6R-[3(E),6α,7β(Z)]]-3-1-[3[-7-[[(2-amino-4-thiazolyl)[carboxy-2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-2-propenyl]-isoquinolinium(R) or (S) or an (R+S) mixture, and

the internal salt of [6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazol)[carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-4-(methylthio)-pyridinium(R) or (S) or an (R+S) mixture

the internal salt of[6R-[3-(E)-6α,7β-[Z,(S*)]]-1-[3-7-[[(2-amino-4-thiazolyl)-[carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium.

the internal salt of[6R-[3-(E)-6α,7β-[Z,(S*)]]-1-[3-7-[[(2-amino-4-thiazolyl)-[carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium.

the internal salt of [6R-[3-(E) 6-α,7-β-(Z)]] 1-[3-[7-[[(2-amino4-thiazolyl) [[carboxy 5-cyano 3,4-dihydroxy2-thienyl)methoxy]imino]acetyl]amino] 2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl] 2-propenyl]quinolinium.

The novel process of the invention for the preparation of a compound offormula I wherein R₇ is M comprises reacting a compound of the formula##STR7## in which R₁, R₂, R₃, R₄ and R₅ are as defined above optionallywith necessary protection of its reactive functions to form an aromaticaldehyde of formula II_(P) : ##STR8## in which R_(1P), R_(2P), R_(3P),R_(4P) and R_(5P) represent R₁, R₂, R₃, R₄ and R₅ as defined previouslyor a protected reactive function, the latter is homologated into anα-hydroxy acid of the formula ##STR9## esterifying the latter to form anα-hydroxy ester of the formula ##STR10## wherein R₁₀ is the remainder ofan easily-cleaveable ester, reacting the latter with N-hydroxyphthalimide to obtain a compound of the formula ##STR11## hydrolysingthe latter to form an O-substituted hydroxylamine of the formula##STR12## condensing the latter with a derivative of(2-amino-thiazolyl)-glyoxylic acid of the formula ##STR13## wherein R₈is hydrogen or a protective group of the amine function to form acompound of the formula ##STR14## amidifying the latter with an ester of7-amino-3-(3-chloro-1-propenyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylicacid hydrochloride of the formula ##STR15## or its salts wherein R₉ isthe remainder of an easily-cleavable ester to obtain a compound of theformula ##STR16## converting the latter into an 3-(3-iodo-propenyl) ofthe formula ##STR17## treating the latter with a base of R₆ to obtain acompound of the formula ##STR18## optionally separating the (E) or(Z)isomers or the (Z) isomers are converted into (E) isomers andsubjecting the compound of formula XII to one or more of the followingreactions in any order:

a) cutting by hydrolysis or by the action of thiourea of all or part ofthe ester groups or the protective groups of the amino or hydroxy,

b) esterification or salification of the carboxylic by a base,

c) salification of amino by an acid,

d) separation of the products in the form of an R,S mixture into R or S.

In a variant of the process, the O-substituted hydroxylamine of formulaVI is condensed with a compound of the formula ##STR19## to obtain theproduct of formula XII as defined previously.

The protected hydroxy functions of R_(1P), R_(2P), R_(3P), R_(4P) andR_(5P) are chosen from acyloxy groups such as formyloxy, acetoxy,propionyloxy, chloroacetoxy, bromoacetoxy, dichloroacetoxy,trichloroacetoxy, trifluoroacetoxy, methoxyacetoxy, phenoxyacetoxy,benzoyloxy, benzoylformoxy, p-nitro benzoyloxy. Other groups includeethoxycarbonyloxy, methoxycarbonyloxy, propoxycarbonyloxy,2,2,2-trichloro ethoxycarbonyloxy, benzyloxycarbonyloxy,tert.-butoxycarbonyloxy, 1-cyclopropyl ethoxycarbonyloxy, phthaloyloxy,butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, oxalyoxy,succinyloxy and pivaloyloxy, phenylacetoxy, phenylpropionyloxy,mesyloxy, chlorobenzoyloxy, para-nitrobenzoyloxy, para-tert-butylbenzoyloxy, capryloyloxy, acryloyloxy, methylcarbamoyloxy,phenylcarbamoyloxy, naphthylcarbamoyloxy.

Other protective groups are phenoxy, 4-chloro phenoxy, tolyloxy ortert.-butyl phenoxy, tetrahydropyrannyloxy, tetrahydrothiopyrannyloxy,methoxytetrahydropyrannyloxy, trityloxy, benzyloxy, 4-methoxy benzyloxy,benzhydryloxy, trichloroethoxy, 1-methyl-1-methoxyethoxy, or alkoxyalkoxy-methyl such as methoxy ethoxy methyl.

Two adjacent hydroxyls can be protected by forming a methylenedioxy,isopropylenedioxy, 1,1-cyclohexyl bis(oxy), diphenylmethylenedioxy,carbonate or hydroxy borannylbis(oxy).

The protected hydroxy functions of R_(1P), R_(2P), R_(3P), R_(4P) andR_(5P), are preferably chosen from methoxyethoxymethoxy,propionyloxymethoxy, acetoxymethoxy, butoxy, isobutoxy, tert.-butoxy,pentoxy, hexyloxy, butyryloxymethoxy, valeryloxymethoxy,pivaloyloxymethoxy, 2-acetoxy ethoxy, 2-propionyloxy ethoxy,1-butyryloxy ethoxy, 2-iodoethoxy, 2,2,2-trichloro ethoxy, vinyloxy,allyloxy, ethynyloxy, propynyloxy, benzyloxy, 4-methoxy, benzyloxy,4-nitro benzyloxy, phenylethoxy, trityloxy, diphenylmethyloxy or3,4-dimethoxyphenoxy. The 2-methoxy ethoxymethoxy (MEM-0) group isparticulary preferred.

The remainders of the easily-clearable ester groups of R₁₀ and R₉ arechosen from butyl, isobutyl, tert.-butyl, pentyl, hexyl, methoxymethyl,ethoxymethyl, isopropoxymethyl, α-methoxy ethyl, α-ethoxy ethyl,methylthiomethyl, ethylthiomethyl, isopropylthiomethyl,pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl,isobutyryloxymethyl, valeryloxymethyl, isovaleryloxymethyl,tert.-butylcarbonyloxymethyl, hexadecanoyloxymethyl, pivaloyloxymethyl,propionyloxyethyl, isovaleryloxyethyl, 1-acetoxy ethyl, 2-acetoxy ethyl,1-propionyloxy ethyl, 2-propionyloxy ethyl, 1-butyryloxy ethyl,2-butyryloxy ethyl, 1-(tert.-butylcarbonyloxy) ethyl, 1-acetoxy propyl,1-hexadecanoyloxy ethyl, 1-propionyloxy propyl, 1-methoxycarbonyloxyethyl, methoxycarbonyloxymethyl, 1-acetoxy butyl, 1-acetoxy hexyl,1-acetoxy heptyl, phthalidyl, 5,6-dimethoxy phthalidyl,tert-butylcarbonylmethyl, vinyl, allyl, 2-chloro allyl, ethynyl,propynyl, methoxycarbonylmethyl, benzyl, 4-methoxy benzyl, 4-nitrobenzyl, phenethyl, trityl, diphenyl methyl, phenyl, 4-chloro phenyl,tolyl, tert.-butyl phenyl, 3,4-dimethoxy phenyl, methoxyethoxymethyl,dimethylaminoethyl, cyanomethyl, tert-butoxycarbonylmethyl,2,2-ethylenedioxy ethyl, cyanoethyl, 2,2-dimethoxy ethyl; 2-chloroethoxymethyl, (2-hydroxy ethoxy) ethyl, 2,3-epoxy propyl 3-dimethylamino2-hydroxy propyl, 2-hydroxy ethyl, 2-methylaminoethoxymethyl, (2-aminoethoxy) methyl, 3-methoxy 2,4-thiadiazol-5-yl, tetrahydropyrann-2-yl,1-methoxy 1-methyl ethyl, 2-hydroxy 1-methyl ethyl, isopropyl,carbamoylmethyl, chloromethyl, 2-chloro ethyl, 2,2,2-trichloro ethyl,2-iodo ethyl, acetyl, methyl, 2-methylthio ethyl, thiocyanatomethyl,2-chloro-1-acetoxy ethyl, 2-bromo 1-acetoxy ethyl, 2-fluoro 1-acetoxyethyl, 2-methoxy 1-acetoxy ethyl, 2-methyl 1-acetoxy propyl, 1-methyl1-acetoxy ethyl, 1-(methoxyacetoxy) ethyl, 1-acetyl carbonyloxyethyl,1-hydroxy acetoxyethyl, 1-(2-thienyl)carbonyloxyethyl, 1-(2-furyl)carbonyloxyethyl, 1-(5-nitro-2-furyl) carbonyloxy-ethyl, 1-(2-pyrrolyl)carbonyloxyethyl, 1-(propionyloxycarbonyloxy) ethyl,1-(propoxycarbonyloxy) ethyl, 1-(isopropoxcarbonyloxy) ethyl,1-(methoxyethoxy-carbonyloxy) ethyl, 1-(allyloxycarbonyloxy) ethyl,isopropoxycarbonyl methyl, 1-[(2,3-epoxy propyl)oxycarbonyloxy] ethyl,1-[(2-furyl)methoxycarbonyloxy ethyl, 1-[(2-fluoro ethoxy)-carbonyloxy]ethyl, 1-(methoxy-carbonyloxy) propyl, 1-(methoxy-carbonyloxy) 1-methylethyl, (methoxycarbonyloxy) chloromethyl,1-(methoxycarbonyl-oxy)-2-chloro ethyl, 1-(methoxy carbonyloxy)2-methoxy ethyl, 1-(methoxycarbonyloxy) allyl or a 5-methyl 2-oxo1,3-dioxol-4-yl remainder.

Diphenylmethyl is preferred for R₁₀ and 4-benzyl methoxy ordiphenylmethyl are preferred for R₉.

The protective group of the amino R₈ can be for example carbamoyl,methyl carbamoyl, phenylcarbamoyl, naphthylcarbamoyl, as well as thecorresponding thiocarbamoyls, alkyl of 1 to 6 carbon atoms substitutedor non-substituted, such as preferably, trichloroethyl, tert.-butyl ortert-amyl, aralkyl such as benzyl, 4-methoxy benzyl, phenethyl, trityl,3,4-dimethoxy benzyl or benzhydryl, a substituted or non-substitutedaliphatic, aromatic or heterocyclic acyl such as formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, chloroacetyl,dichloroacetyl, trichloroacetyl, bromoacetyl, trifluoroacetyl benzoyl,toluolyl, naphthoyl, chlorobenzoyl, para-nitro benzoyl, para-tert-butylbenzoyl, phenoxyacetyl, caprylyl, decanoyl, acryloyl, phthaloyl, mesyl,phenyl-acetyl, phenylpropionyl, oxalyl, succinyl, pivaloyl, loweralkoxycarbonyl or cycloalkoxycarbonyl such as methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,pentoxycarbonyl, hexyloxycarbonyl, trichloroethoxy carbonyl,aralkoxycarbonyl such as benzyloxycarbonyl. The trityl is preferred.

The above list is not limitative and it is evident that other amineprotective groups, groups known in particular in the chemistry of thepeptides, can also be used.

The hydrolysis of the compound of formula V can be made by methods knownin the art.

The functional derivative of the acid of formula VIII may be for examplea halide, a symmetrical or mixed anhydride, amide, azide or an activatedester. An example of a mixed anhydride is that formed with isobutylchloroformate or that formed with pivaloyl chloride and thecarboxylic-sulfonic mixed anhydrides formed for example with p-toluenesulfonyl chloride.

An example of an activated ester is the ester formed with2,4-dinitrophenol or that formed with hydroxybenzothiazole. An exampleof a halide is the chloride or bromide.

The anhydride can be formed in situ by the action of N,N'-disubstitutedcarbodiimide, for example, N,N-dicyclohexylcarbodiimide. The acylationreaction is preferably carried out in an organic solvent such asmethylene chloride but other solvents can be used such astetrahydrofuran, chloroform or dimethylformamide.

When an acid halide is used and in a general manner when a hydrohalicacid molecule is released during the reaction, the reaction ispreferably carried out in the presence of a base such as sodiumhydroxide, potassium hydroxide, sodium or potassium carbonates andbicarbonates, sodium acetate, triethylamine, pyridine, morpholine orN-methylmorpholine. The reaction temperature is generally lower than orequal to ambient temperature.

A product of formula VIII can also be reacted directly with a product offormula IX in the presence of a carbodiimide such asdiisopropylcarbodiimide or 1-(3-dimethylamino propyl)-3-ethylcarbodiimide (EDC).

The action of the reagent capable of introducing R₆ into the product offormula XI is carried under the following conditions: When Hal ischlorine, a substitution of chlorine by iodine in the presence of sodiumiodide can be carried out in situ or separately, then the desiredreagent is added in the optional presence of an organic solvent such asdichloromethane, acetonitrile or tetrahydrofuran. The desired reagent ofR₆ can also be reacted directly on the product of formula X in thepresence of silver tetrafluoroborate.

The isomerism of the products of formula XII can be different from thatof the products of formula X or XI used at the start. When the Z isomeris isolated, this isomer can be converted into the E isomer by the usualmethods, notably by the action of iodine.

Depending upon R₈, R₁₀, R₉, R_(1P), R_(2P), R_(3P), R_(4P) and R_(5P),the action of one or more of hydrolysis, hydrogenolysis agents or ofthiourea on the product of formula XII is intended to eliminate R₈ whenthe latter is a protective group of the amino to convert R_(1P), R_(2P),R_(3P), R_(4P) and R_(5P) into R₁, R₂, R₃, R₄ and R₅ respectively whenthese are a protective group of hydroxyls and/or to eliminate R₁₀ and R₉when these are easily-cleavable ester groups, one of those that it isdesired to eliminate.

It is possible to eliminate R₈ and to convert R_(1P), R_(2P), R_(3P),R_(4P) and R_(5P) into R₁, R₂, R₃, R₄ and R₅ respectively when these area protective group of hyroxyls without affecting R₁₀ and R₉ when thesehave to be preserved. The nature of the reagents to be used in such acase is well known to one skilled in the art. Examples of such reactionsare given further on in the experimental part. A description of themethods for eliminating the different protective groups will be found inFrench Patent Application No. 2,499,995.

Given the nature of the preferred protective groups used: trityl for R₈,2-methoxyethoxymethyl to protect hydroxy functions of R₁, R₂, R₃, R₄ andR₅, diphenylmethyl for R₁₀ and 4-methoxy benzyl or diphenylmethyl forR₉, trifluoroacetic acid is preferably used without a solvent or in asolvent such as anisole or a mixture of solvents such asanisole/methylene chloride. A salt is then obtained with trifluoroaceticacid and the free base can be obtained by the action of a base such astriethylamine carbonate.

The salification of the products can be carried out by the usualmethods. For example, by the action, on a product in the acid form or ona solvate, for example the ethanolic solvate or a hydrate of this acid,of a mineral base such as sodium or potassium hydroxide, sodium orpotassium carbonate or bicarbonate. Mineral acid salts such as trisodiumphosphate can also be used. Organic acid salts can also be used such as,for example, sodium salts of saturated or unsaturated, linear orbranched aliphatic carboxylic acids of 1 to 18 and preferably 2 to 10carbon atoms. The aliphatic chains of these acids can be interrupted byone or more heteroatoms such as oxygen or sulfur or substituted by arylsuch as phenyl, thienyl or furyl, by one or more hydroxyl or by one ormore halogens such as fluorine, chlorine or bromine, preferablychlorine, by one or more lower carboxylic or alkoxycarbonyl, preferablymethoxycarbonyl, ethoxycarbonyl or propyloxycarbonyl, by one or morearyloxy, preferably phenoxy.

Moreover, sufficiently soluble aromatic acids can be used as the organicacids such as benzoic acid substituted preferably by lower alkyl.

Examples of such organic acids are formic acid, acetic acid, acrylicacid, butyric acid, adipic acid, isobutyric acid, n-caproic acid,isocaproic acid, chloropropionic acid, crotonic acid, phenyl acetic,(2-thienyl) acetic acid, (3-thienyl) acetic acid, (4-ethyl phenyl) acid,acetic acid, glutaric acid, monoethylic ester of adipic acid, hexanoicacid, heptanoic, acid, decanoic acid, oleic acid, stearic acid, palmiticacid, 3-hydroxy propionic acid, 3-methoxy propionic acid, 3-methylthiobutyric acid, 4-chloro butyric acid, 4-phenyl butyric acid, 3-phenoxybutyric acid, 4-ethyl benzoic acid, 1-propyl benzoic acid.

Sodium acetate, sodium 2-ethyl hexanoate or sodium diethyl acetate arepreferably used as sodium salts.

The salification can also be obtained by the action of an organic basesuch as triethylamine, diethylamine, trimethylamine, propylamine,N,N-dimethyl ethanolamine; tris[(hydroxymethyl)-amino] methane,methylamine, ethanolamine, pyridine, picoline, dicyclohexyl amine,morpholine and benzylamine or by the action of arginine, lysine,procaine, histidine, N-methyl glucamine. This salification is preferablycarried out in a solvent or a mixture of solvents such as water, ethylether, methanol, ethanol or acetone.

The salts are obtained in amorphous or crystallized form according tothe reaction conditions used. The crystallized salts are preferablyprepared by reacting the free acids with one of the salts of thealiphatic carboxylic acids mentioned above, preferably with sodiumacetate. The salification of the products by mineral or organic acids iscarried out under the usual conditions.

The optional esterification of the proucts is carried out under standardconditions. The operation is generally carried out by reacting the acidof formula I or a functional derivative of the acid with a derivative ofthe formula

    Z--Re

wherein Z is hydroxyl or halogen such as chlorine, bromine, iodine andRe is the ester group to be introduced, a non-exhaustive list of whichgroup is given above. In certain cases, it may be advantageous to carryout an esterification on a product of which the amine and/or reactivegroups present on the oxyimino are blocked before removing theprotective group of the same amine and of the reactive group present onthe oxyimino.

The novel process for the preparation of the compounds of formula Iwherein R₇ is K or L comprises reacting an ester of the formula##STR20## wherein X' is a leaving group or a radical capable ofgenerating a leaving group in situ, R_(7P) is R₇ as defined above inwhich the hydroxy or the amino are protected and R₁₀ is the remainder ofan easily cleavable ester with N-hydroxy phtalimide optionally in thepresence of an activating agent to obtain a compound of the formula##STR21## hydrolyzing the latter into the O-substituted hydroxylamine ofthe formula ##STR22## condensing the latter with a derivative of(2-amino thiazol-4-yl)-2-oxoacetic acid of the formula ##STR23## whereinR₈ is hydrogen or a protective group of the amine function to obtain thederivative of the α-alkoxy imino acetic acid of the formula ##STR24##optionally preparing a functional -derivative of the latter, amidifyingthe product of formula VI' or functional derivative with an ester of thehydrochloride of7-amino-3-(3-halogeno-1-propenyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylicacid of the formula ##STR25## or its salts, wherein Hal is halogen andR₉ is the remainder of an easily cleavable ester to obtain a derivativeof 7-(N-substituted amido)3-(3-halo-1-propenyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid of the formula ##STR26## optionallyconverting the latter into the analogous 3-(3-iodopropenylated) productof the formula ##STR27## with a base of treating the latter formula R₆to obtain a product of the formula ##STR28## from which product offormula X' optionally isolating the (E) or (Z) isomers or the Z isomersare converted into the E isomer and which product of formula X' issubjected to one or more of the following reactions, in any order:

a) cutting by hydrolysis or by the action of thiourea of all or part ofthe ester groups or protective groups of the amino or the hydroxyl,

b) esterification or salification by a base of the carboxylic,

c) salification by an acid of the amino,

d) separation of the products in the form of an R,S mixture into R or S.

A variant of the process described above comprises condensingO-substituted hydroxylamine of formula IV' with a product of the formula##STR29## to form a compound of formula X'.

In the above process and in its variant, the protecting groups of thehydroxy and amino functions contained in R_(7P) are chosen from the samegroups as those mentioned above for R_(1P), R_(2P), R_(3P), R_(4P),R_(5P) and R₈.

Diphenylmethyl is prefered for R₁₀ and 4-methoxybenzyl or diphenylmethylis prefered for R₉.

Trityl is prefered for R₈ and benzyloxycarbonyl is prefered for R_(7P).

The X group can be a hydroxy radical, an alkylsulfonyloxy radical suchas methylsulfonyloxy, an arylsulfonyloxy radical such as phenyl ortolylsulfonyloxy, or a halogen atom such as chlorine, bromine or iodine.The hydroxy and chloro values are more particularly prefered.

The hydrolysis of III',

the preparation of the functional derivative of the acid VI',

the acylation reaction,

the introduction of the R₆ radical,

the optional transformation of an obtained isomer,

the action of a hydrolysis reagent or of the thiourea,

the elimination of the R₈ group,

the transformation of the R_(7P) group into R₇ group,

the salification of the products,

the optional esterification,

the resolution of the diastereoisomers: can be made in the sameconditions and prefered conditions as those mentioned above for thepreparation of the compounds of formula I wherein R₇ is M

The products of formula I contain several asymetrical carbons. In thecephem nucleus which contains two asymetrical carbons, the two carbonsare in R configuration. Furthermore, the substituent present on theoxyimino function also contains an asymetrical carbon which can be in Ror S form or in the form of an R+S mixture. The separation of the twodiastereoisomers can be carried out by means of a man skilled in theart, for example by chromatography.

The compounds of formula II' are new and can be prepared by reacting acompound of the formula

    R'.sub.7 --CHO                                             XII'

of which the reactive functions are if necessary protected to obtain acompound of the formula

    R'.sub.7P --CHO                                            XIII'

converting the derivative of formula XII' or XIII' into the α-hydoxyacid derivative of the formula ##STR30## which can be optionallyconverted into a corresponding halogenated or alkyl- or arylsulfonylatedderivative, which is then esterified.

The derivatives of formula II' in which X' is halogen can in apreferential manner be obtained by a process according to which analdehyde of formula XII' or XIII' is treated with malonodinitrile toobtain a compound of the formula ##STR31## which is subjected to theaction of an oxidizing agent to obtain an epoxide of the formula##STR32## which is treated with a hydrohalic acid to obtain the acid ofthe formula ##STR33## which is esterified.

The derivatives of formulae III', IV', VI', VIII', IX' and X', as wellas the derivatives of formulae XIV, XV, XVI and XVII are also new.

The compounds of formula II' in which X' hydroxy can also be prepared bya process in which a compound of the formula

    R.sub.7P --CH.sub.2 --COOR.sub.3                           XVIII

is subjected to the action of an oxidizing agent to obtain a ketonicderivative of the formula ##STR34## which is reduced to thecorresponding secondary alcohol of formula II'.

The compounds of formula XII' are known, for example, from the C.A. Vol.111,P194772, Vol. 108,P150482, Vol. 101,P38342, Vol. 97P215983, Vol.95P203734 or also J. Am. Chem. Soc., Vol. 73, p. 2956 (1951), or can beprepared by methods known to an average man skilled in the art, startingwith the compounds described in these references.

As for the compounds of formula XVIII and the corresponding acid, theyare described in European Patent Application No. 136,721, as well as J.of Antibiotics, Vol. 36, No. 8, p. 1020 (1983). In a general manner, thecompounds of formula XVIII can be prepared from the acid by methodsknown to an average man skilled in the art.

The antibacterial compositions of the invention are comprised of anantibactericidally effective amount of at least one compound of formulaI or its non-toxic, pharmaceutically acceptable acid addition salts andan inert pharmaceutical carrier. The compositions may be in the form oftablets, dragees, capsules, granules, suppositories, ointments, creams,gels and injectable solutions.

Examples of inert pharmaceutical carriers are talc, arabic gum, lactose,starch magnesium stearate, cocoa butter, aqueous or non-aqueousvehicles, fatty derivatives of animal or vegetable origin, paraffinderivatives, glycols, various wetting agents, dispersants andemulsifiers and preservatives.

When in the form of a powder, the compositions are dissolvedextemporaneously in a vehicle such as apyrogenic water.

The compositions have a very good antibiotic activity on gram (+)bacteria such as staphylococci, streptococci and notably onpenicillin-resistant staphylococci. Their effectiveness on gram (-)bacteria, particularly on coliform bacteria, klebsiella, salmonella,proteus and pseudomonas, is particularly remarkable.

These properties make the compositions suitable for use as medicamentsin the treatment of germ-sensitive diseases and particularly in that ofstaphylococci, such as staphylococci septicemias, malignantstaphylococcia of the face or skin, pyodermititis, septic or suppurativesores, anthrax, phlegmon, erysipelas, acute primary or post-influenzalstaphylococcia, bronocho-pneumonia, pulmonary suppurations. Thesecompositions can also be used as medicaments in the treatment ofcolibacilloses and associated infections, of proteus, klebsiella andsalmonella infections and of other diseases caused by gram (-) bacteria.

The compositions wherein A is a cleavable ester are preferred for oraladministration and when in the form of a powder, the compositions aredissolved extemporaneously in a vehicle such as apyrogenic water.

The novel method of combatting bacterial infections in warm-bloodedanimals, including humans, comprises administering to warm-bloodedanimals an antibacterially effective amount of at least one compound offormula I or its non-toxic, pharmaceutically acceptable acid additionsalts. The compounds may be administered orally, rectally, parenterallyor topically on skin and mucous membranes. The usual daily dose is 3 to50 mg/kg depending on the condition treated, specific compound used andthe method of administration. The method can also be used fordisinfecting surgical instruments.

The novel intermediates of the invention are those compounds of formulaeIII, III', IV, IV', V, V', VI, VI', VIII, VIII', IX', X, X', XI, XII,XIII as well as the derivatives of the formulae XIV, XV, XVI and XVII.

The compound of formula VI in which R_(1P) and R_(2P) are fluorine andR_(3P) and R_(4P) are a hydroxy protected by a methoxyethoxymethyl(M.E.M.) (hereafter) product of formula VI_(A) may be prepared byreacting a compound of the formula ##STR35## wherein Alk is alkyl,preferably methyl, with butyllithium and trimethylborate and thenoxygenated water to obtain a compound of the formula ##STR36## reactingthe latter with dimethylamine in the presence of formic anhydride toobtain a compound of the formula ##STR37## reacting the latter withmethyl iodide and hexamethylenetetramine in the presence of acetic acidto obtain a compound of the formula ##STR38## reacting the latter toeliminate the alkyl in the presence of borontribromine to obtain thecompound of the formula ##STR39## reacting the latter with a protectingagent to protect the hydroxyl function by a MEM group for example toobtain a compound of the formula ##STR40## wherein PG represents aprotective group of the hydroxyls, reacting the latter with aorganophosphorated derivative of the formula ##STR41## wherein Alk₁ andAlk₂ are individually alkyl of 1 to 4 carbon atom to obtain a compoundof the formula ##STR42## reacting the latter with a reducing agent i.e.diisobutyl-aluminium hydride to obtain a compound of the formula##STR43## reacting the latter with an epoxidation reagent, i.e. withm-chloroperbenzoic acid to obtain a compound of the formula ##STR44##reacting the latter with cuprous chloride in the presence of lithiumchloride to obtain a compound of the formula ##STR45## reacting thelatter with an oxidation reagent i.e. sodium meta-periodate then with anesterifying reagent to obtain a compound of the formula ##STR46##wherein R₁₀ has the above definition and reacting the latter withN-hydroxyphthalimide to obtain a compound of the formula ##STR47##

The products of formulae II and A are known in a general manner and mostare commercially available. Others can be prepared fromcommercially-available products by the methods described in thepreparations below for the preparation of the compound of formula II.The methods described in the literature can also be used, notably theso-called Rosemund reduction, the reduction of benzoic acid or theformylation of aromatic rings such as the Vilsmeier-Haack reaction, theGatterman-Koch reaction, the Reimer-Tiemann reaction or the reactionwith formyl fluoride (J. Am. Chem. Soc., Vol. 82, p. 2380 (1960)).

The products of formulae VII and IX are also knwon in the literature,notably in Belgian Patent Application No. 864,828 and European PatentApplication EP 0,333,154.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

PREPARATION 1 2-chloro-3,4-bis[(2-methoy-ethoxy)-methoxy]-benzaldehyde

STEP A: 2-chloro-3,4-dihydroxy benzaldehyde

27.62 g of 3,4-dihydroxy benzaldehyde (commercial) were dissolved in 450ml of acetic acid and chlorine was bubbled through the solution at anordinary temperature until 4.48 ml of the gas had been consumed. Themixture was stirred for 16 hours and then the solution was concentratedand cooled to 0° C. The precipitate was filtered, washed and dried toobtain 7.5 g of the expected product which after it was crystallizedfrom ethyl acetate melted at 196° C.

STEP B: 2-chloro-3,4-bis[(2-methoxy-ethoxy)-methoxy]-benzaldehyde

46 ml of diisopropyl ethylamine were added to a suspension of 11.42 g ofthe product of Step A in 120 ml of methylene chloride and the mixturewas cooled to -10° C. Then, 30.14 ml ofchloro-(2-methoxy-ethoxy)-methane were added and the mixture was stirredfor one hour. The mixture was diluted with 100 ml of water, separatedand then the organic phase was washed, dried and concentrated to obtain22.6 g of the expected product with a Rf=0.6 (eluant: ethyl acetate).

NMR analysis of the proton (CDCl₃ 250 MHz in ppm): 3.36 (s), and 3.38(s): --OCH₃ 3.58 (m) (4H), 3.84 (m) (2H) and 4.06 (m) (2H): --O--CH₂--CH₂ --O 5.29 (s) (2H) and 5.38 (s) (2H): --O--CH₂ --O 7.21 (d) and7.71 (d): aromatic protons (Ar--H) 10.36 (s): --CH═O.

PREPARATION 2 3-formyl-5,6-bis[(2-methoxy-ethoxy)-methoxy]-benzonitrile

STEP A: 3-formyl-6-hydroxy-5-methoxy benzonitrile

A mixture of 23.1 g of 3-bromo-4-hydroxy-5-methoxy benzaldehyde, 9.3 gof cuprous cyanide and 140 ml of dimethyl acetamide (DMA) was refluxedfor 2 hours with stirring. After cooling, the mixture was poured overice and extracted with an ethyl acetate-methanol mixture (90-10). Theorganic phase was washed and dried and the solvents were eliminated toobtain 18 g of crude product, which was used as is for the followingstep. It melted at 180° C.

STEP B: 3-formyl-5,6-dihydroxy benzonitrile

18 g of the product of Step A and 400 ml of dichloromethane were mixedtogether under nitrogen and the mixture was cooled to 0° C. 150 ml of amolar solution of boron tribromide in dichloromethane were added and themixture stood for one night at ambient temperature. It was concentrated,cooled again to 0° C. and 250 ml of a normal solution of hydrochloricacid were added. The crystallized product was separated out, washed withwater, dried then crystallized from an isopropanol-water mixture (1-2)to obtain 12 g of the expected product.

Infrared analysis (Nujol): Strong and complex absorption in the --NH/OHregion 2245 cm⁻¹ : C═N 1700 cm⁻¹ : C═O 1602, 1597 1520 cm⁻¹ : aromaticnucleus

NMR analysis of the proton (DMSO 250 MHz in ppm): 7.45 (d) (J=2): Ar--H7.73 (d) (J=2): Ar--H 9.74: CH═O 11.15: mobile absorption

STEP C: 3-formyl-5,6-bis[(2-methoxy-ethoxy)-methoxy]-benzonitrile

53.6 ml of diisopropyl ethylamine were added to a suspension of 12.6 gof the product of Step B in 500 ml of dichloromethane and the mixturewas cooled to -10° C. Then 35.3 ml of chloro-(2-methoxy-ethoxy)-methanewere added and the mixture was stirred for one hour. The medium wasdiluted with 100 ml of water, separated and then the organic phase waswashed, dried and concentrated to obtain 21.4 g of the expected product.

Infrared analysis (CHCl₃): Absence of OH 2235 cm⁻¹ : C═N 1702 and 2730cm⁻¹ : CH═O 1592, 1582 and 1485 cm⁻¹ : aromatic nucleus

NMR analysis of the proton (CDCl₃ 250 MHz in ppm): 3.37 (s): --OCH₃ 3.58(m) (4H), 3.85 (m) (2H) and 4.06 (m) (2H): O--CH₂ --CH₂ --O 5.39 (s)(2H) and 5.49 (s) (2H): --O--CH₂ --O 7.76 (d) (1H) and 7.92 (d) (1H):Ar--H 9.90 (s): --CH═O

PREPARATION 3 3-fluoro-4,5-bis[(2-methoxy-ethoxy)-methoxy] benzaldehyde

STEP A: 3-fluoro-4-hydroxy-5-methoxy benzaldehyde

A mixture of nitrogen containing 10% of fluorine was bubbled for two anda half hours through a mixture of 30.4 g of 4-hydroxy-5-methoxybenzaldehyde (vanillin), 100 ml of acetonitrile and 250 ml of Freon at0° C. under nitrogen. After treatment with thiosulfate, acidificationwith a solution of 2N hydrochloric acid and extraction with ethylacetate, the organic phase was washed, dried, concentrated andchromatographed on silica eluting with dichloromethane to-obtain 2.1 gof the desired product with a Rf=0.3.

Analysis: C₇ H₇ FO₃ Calculated: %C 56.47 %H 4.14 %F 11.16 Found: 56.44.1 11.0

STEP B: 3-fluoro-4,5-dihydroxy benzaldehyde

3.72 g of the product of Step A and 60 ml of dichloromethane were mixedtogether under nitrogen and the mixture was cooled to 0° C. 32 ml of amolar solution of boron tribromide in dichloromethane were added and themixture stood for one hour at ambient temperature and then wasconcentrated, cooled again to 0° C. and acidified. The crystallizedproduct was separated out, washed with water and dried to obtain 2.83 gof the expected crude product which is used as is for the followingstep. It had a Rf=0.2 [eluant: acetone-dichloromethane (1-9)].

STEP C: 3-fluoro-4,5-bis[(2-methoxy-ethoxy)-methoxy] benzaldehyde

17 ml of diisopropyl ethylamine were added to a suspension of 2.8 g ofthe product of Step B in 5.6 ml of dichloromethane. The mixture wascooled to 10° C. and then 6.5 ml of chloro-(2-methoxy-ethoxy)-methanewere added. The mixture was stirred for one hour and was then dilutedwith 100 ml of water and separated. Then, the organic phase was washed,dried and concentrated to obtain 5.5 g of the expected product with aRf=0.55 [eluant: dichloromethane-acetone (9-1)].

Infrared analysis (CHCl₃): Absence of OH 1696 and 2730 cm⁻¹ : conjugatedCH═O

NMR analysis of the proton (CDCl₃ 200 MHz in ppm): 3.36 (s) and 3.37(s): --OCH₃ 3.60 (m) (4H), 3.85 (m) (2H) and 3.96 (m) (2H): O--CH₂ --CH₂--O 5.33 (s) and 5.36 (s): O--CH₂ --O 7.32 (dd) 7.51 (m): Ar--H 9.90(m): --CH═O

PREPARATION 4 3-chloro-4,5-bis[(2-methoxy-ethoxy)-methoxy]-benzaldehyde

STEP A: 3-chloro-4,5-dihydroxy benzaldehyde

37.2 g of commercial 5-chloro vanillin and 800 ml of dichloromethanewere mixed together under nitrogen and cooled to 0° C. 300 ml of a molarsolution of boron tribromide in dichloromethane were added and themixture stood for one night at ambient temperature. It was concentrated,cooled again to 0° C. and acidified. The crystallized product wasseparated, washed with water, dried and crystallized from anisopropanol-water mixture (1-2 by volume) to obtain 26.6 g of theexpected product melting at >260° C.

Infrared analysis (Nujol): 3425 cm⁻¹ : --OH+general absorption 1672-1660cm⁻¹ : C═O 1595, 1588, 1534, 1500 cm⁻¹ : aromatic ring

NMR analysis of the proton (DMSO 250 MHz in ppm): 7.24 (d J=2 Hz) and7.44 (d J=2 Hz): Ar--H 9.90 (m): --CH═O 10.40: mobile absorption

STEP B: 3-chloro-4,5-bis[(2-methoxy-ethoxy)-methoxy] benzaldehyde

60.5 ml of diisopropyl ethylamine were added to a suspension of 15 g ofthe product of Step A in 150 ml of dichloromethane and the mixture wascooled to -10° C. Then, 39.7 ml of chloro-(2-methoxy-ethoxy)-methanewere added over 45 minutes and the mixture was stirred for half an hourand diluted with 100 ml of water and separated. Then, the organic phasewas washed, dried, concentrated and chromatographed on silica, elutingwith a dichloromethane-methanol mixture (99-1) to obtain 15.9 g of theexpected product.

Infrared analysis (CHCl₃): 1698 and 2735 cm⁻¹ : conjugated CH═O 1591,1579, 1498 cm⁻¹ : aromatic ring

NMR analysis of the proton (CDCl₃ 250 MHz in ppm): 3.38 (s): --OCH₃ 3.57(m) (4H), 3.87 (m) (2H) and 4.03 (m) (2H): O--CH₂ --CH₂ --O 5.36 (s) and5.38 (s): O--CH₂ --O 7.59 (d) 7.62 (d): Ar--H 9.85: --CH═O

PREPARATION 5 3-nitro-4,5-bis[(2-methoxy-ethoxy)-methoxy] benzaldehyde

STEP A: 3-nitro-4,5-dihydroxy benzaldehyde

35 g of 5-nitro vanillin (commercial) and 1200 ml of dichloromethanewere mixed together under nitrogen and the mixture was cooled to 0° C.533 ml of a molar solution of boron tribromide in dichloromethane wereadded and the mixture stood for 2 days at abmient temperature and thenwas concentrated. The residue was taken up cold (ice bath+methanol) in300 ml of 2N hydrochloric acid and the mixture was stirred for two tothree hours at this temperature, then left for 16 hours at ambienttemperature. Extraction was carried out with ethyl acetate and theorganic phase was washed, dried and concentrated to obtain 18 g of theexpected product melting at >260° C.

Infrared analysis (Nujol): general absorption NH/OH 1682 cm⁻¹ : C═O1620, 1590, 1580, 1548 and 1525 cm⁻¹ : aromatic ring+--NH₂

STEP B: 3-nitro-4,5bis[(2-methoxy-ethoxy)-methoxy] benzaldehyde

13.6 ml of diisopropyl ethylamine were added to a suspension of 18 g ofthe product of Step A in 50 ml of dichloromethane and the mixture wascooled. Then, 39.6 ml of chloro-(2-methoxy-ethoxy)-methane were addedover 45 minutes and was then stirred for two hours at 0° C. and dilutedwith 100 ml of water and separated. The organic phase was washed, dried,concentrated and chromatographed on silica, eluting with adichloromethane-acetone mixture (9-1) to obtain 22.1 g of the expectedproduct with a Rf=0.3.

Infrared analysis (CHCl₃): 1704 cm⁻¹ : CH═O 1608, 1578, 1546, 1496 cm⁻¹: aromatic ring+--NO₂

NMR analysis of the proton (CDCl₃ 300 MHz in ppm): 3.36 and 3.38: --OCH₃3.55 (m), 3.87 (m): O--CH₂ --CH₂ --O 5.41: O--CH₃ --O 7.92: Ar--H 9.93:--CH═O

PREPARATION 6 3-iodo-4,5-bis[(2-methoxy-ethoxy)-methoxy] benzaldehyde

STEP A: 3-iodo-4,5-dihydroxy benzaldehyde

37.2 g of 5-iodo vanillin (commercial) and 360 ml of dichloromethanewere mixed together under nitrogen and the mixture was cooled to 0° C.135 ml of a molar solution of boron tribromide in dichloromethane wereadded and the mixture stood for 16 hours at ambient temperature and wasthen concentrated, cooled to 0° C. and acidified. The crystallizedproduct was separated out, washed with water, dried and crystallizedfrom an isopropanol-water mixture (1-2 by volume) to obtain 23.4 g ofthe expected product.

Infrared analysis (Nujol): general absorption NH/OH 1662 (m) 1640 (F)cm⁻¹ : C═O 1588, 1578, 1516 cm⁻¹ : aromatic ring

NMR analysis of the proton (DMSO 250 MHz in ppm): 7.25 (sl) and 7.44(sl): Ar--H 9.68 (m): --CH═O 10.46, 1043 cm⁻¹ : mobile absorption

STEP B: 3-iodo-4,5-bis[(2-methoxy-ethoxy)-methoxy] benzaldehyde

67 ml of diisopropyl ethylamine were added to a suspension of 25.4 g ofthe product of Step A in 640 ml of dichloromethane and the mixture wascooled to 10° C. Then, 44 ml of chloro-(2-methoxy-ethoxy)-methane wereadded over 45 minutes and the mixture was stirred for half an hour,diluted with 100 ml of water and was separated. Then, the organic phasewas washed, dried, concentrated and chromatographed on silica, elutingwith an ethyl acetate-hexane mixture (1/1) to obtain 25.5 g of theexpected product.

Infrared analysis (CHCl₃): Absence of OH 1698 and 2730 cm⁻¹ : CH═O 1588,1562, cm⁻¹ : aromatic ring

NMR analysis of the proton (CDCl₃ 250 MHz in ppm): 3.38 (sl) (6H):--OCH₃ 3.58 (m) (4H), 3.84 (m) (2H) and 4.05 (m) (2H): O--CH₂ --CH₂ --O5.33 (sl) and 5.39 (sl): O--CH₂ --O 7.68 (sl) and 7.96 (sl): Ar--H 9.82:--CH═O.

PREPARATION 7 3,4,5,tris[(2-methoxy-ethoxy)-methoxy] benzaldehyde

52 ml of diisopropyl ethylamine were added to a suspension of 8 g of3,4,5-trihydroxy benzaldehyde (commercial) in 160 ml of dichloromethaneand the mixture was cooled to 0° to 5° C. Then, 35 ml ofchloro-(2-metoxy-ethoxy)-methane were added over one and a half hoursand the mixture was stirred, diluted with 100 ml of water and separated.The organic phase was washed, dried and concentrated to obtain 21.75 gof crude product which was used as is for what follows.

Infrared analysis (CHCl₃): Absence of OH 1696 cm⁻¹ : CH═O 1590, 1498cm⁻¹ : aromatic ring

NMR analysis of the proton (CDCl₃ 250 MHz in ppm): 3.36 and 3.38 (9H):--OCH₃ 3.57 (m) (6H), 3.85 (m) (4H) and 3.99 (m) (2H): --O--CH₂ --CH₂--O 5.31 (w) (2H) and 5.34 (s) (4H): O--CH₂ --O 7.43 (s): Ar-- H 9.82:--CH═O 5.31 (w) (2H) and 5.34 (s) (4H): O--CH₂ --O 7.43 (s): Ar--H 9.82:--CH═O

PREPARATION 8 2,5-dichloro-3,4-bis [(2-methoxy-ethoxy)-methoxy]benzaldehyde

STEP A: 2,5-dichloro-3,4-dihydroxy benzaldehyde

27.6 g of 3,4-dihydroxy benzaldehyde (commercial) were dissolved in 300ml of acetic acid and chlorine was bubbled through the solution at anordinary temperature until 31.24 g of the gas had been consumed. Themixture was stirred for 42 hours and then was concentrated, cooled to 0°C. The precipitate was filtered, washed and dried to obtain 13.7 g ofthe expected product melting at 176° to 178° C. with a Rf=0.1 [eluant:ethyl acetate-cyclohexane (5-5)]

NMR analysis of the proton (DMSO 250 MHz in ppm): 7.24 (d J=2 Hz) and7.44 (d J=2H): Ar--H 9.90 (m): --CH═O 10.40: mobile absorption

STEP B: 2,5-dichloro-3,4-bis[(2-methoxy-ethoxy)-methoxy] benzaldehyde

60.5 ml of diisopropyl ethylamine and then 11.27 ml ofchloro-(2-methoxy-ethoxy)-methane were added to a solution of 6.83 g ofthe product of Step A in 265 ml of acetonitrile. The mixture was stirredfor two hours at 35° C. and was evaporated to dryness. The residue wastaken up in dichloromethane, washed, dried and the solvent wasevaporated. Chromatography was carried out on silica, eluting with anethyl acetate-cyclohexane mixture (6-4) to obtain 10.9 g of the expectedproduct melting at 50° C. with a Rf=0.3.

Infrared analysis (PE 580): 1690 cm⁻¹ : CH═O 1572, 1551 cm⁻¹ : aromaticring

NMR analysis of the proton (CDCl₃ 250 MHz in ppm): 3.37 and 3.38: --OCH₃3.58 and 4.01 (m) (2H): O--CH₂ --CH₂ --O 5.29 and 5.36 (s): O--CH₂ --O7.78 (s): Ar--H 10.36 (s): --CH═O

PREPARATION 9 3-methoxy-4,5-bis[(2-methoxy-ethoxy)-methoxy] benzaldehyde

34 ml of diisopropyl ethylamine were added to a suspension of 8 g of3,4-dihydroxy-5-methoxy benzaldehyde (commercial) in 80 ml ofdichloromethane and the mixture was cooled to -5° C. to -10° C. Then, 23ml of chloro-(2-methoxy-ethoxy)-methane were added over half an hour andthe mixture was stirred for 16 hours. The organic phase was washed,dried, filtered, concentrated and chromatographed on silica, elutingwith a hexane -ethyl acetate mixture (50-50) to obtain the expectedproduct with a Rf=0.4 [eluant: hexane-ethyl acetate (30-70)].

Infrared analysis (CHCl₃ on PE 580): Absence of OH 1696 cm⁻¹ : CH═O 588,1498 cm⁻¹ : aromatic ring

NMR analysis of the proton [CDCl₃ 250 MHz in ppm): 3.36 (s) (3H) and3.38 (s) (3H): O--CH₂ --CH₂ --OCH₃ 3.57 (m) (4H), 3.87 (m) (2H) and 4.00(m) (2H): O--CH₂ --CH₂ --O 3.90 (s) (3H): Ar--OCH₃ 5.31 (s) (2H) and5.35 (s) (2H): O--CH₂ --O 7.19 (d J=2 Hz) (1H) and 7.38 (d J=2 Hz) (1H):Ar--H in the meta position 9.80 (s) (1H): --CH═O

PREPARATION 101-[3-[7β-[oxo-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0][oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b] pyridinium iodide

STEP A: 4-methoxy-benzyl7β-[oxo-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z+E)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylate

5 g of 4-methoxy benzyl 7β-amino-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylatehydrochloride (European Patent Application No. 0,333,154) and 0.72 g ofoxo-[2-[(triphenylmethyl)-amino]-thiazol-4-yl] acetic acid (BelgianPatent Application No. 864,828) in 200 ml of dichloromethane werestirred under nitrogen and the mixture was cooled to 0° C. Then, 2.315 gof 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC) were added,followed by stirring for 40 minutes, washing and drying. The solventswere evaporated and the residue was chromatographed, eluting with adichloromethane-isopropyl ether mixture (9-1) to obtain 5.51 g of theexpected product with a Rf=0.3.

STEP B: 4-methoxy benzyl7β-[oxo-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z+E)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylate

5.5 g of the product of Step A were dissolved in 110 ml of acetone and3.094 g of sodium iodide were added. The mixture was stirred for one anda half hours at 20° C. and the solvent was evaporated. The residue wastaken up in 350 ml of dichloromethane, washed, dried, filtered andbrought to dryness. The foam was filtered and the residue waschromatographed, eluting with a dichloromethane -isopropyl ether mixture(90-10) to obtain 3.93 g of the expected iodine with a Rf=0.3.

Infrared analysis (CHCl₃) 1786, 1721, 171 and 1633 cm⁻¹ : C═O andβ-lactam 1613, 1586, 1535, 1516 cm⁻¹ : aromatic+conjugated system

NMR analysis of the proton (CDCl₃ 300 MHz in ppm): 3.57: --S--CH₂--C(C═CH--)═C-- 3.82 (s): Ar--OCH₃ 3.98 (d, J=8): --CH═CH--CH₂ --I 5.03(d J=5) ppm: CO--NH--CH(C═O)--CH--(N--)--S-- 5.25 (AB, J=12): CO--O--CH₂--Ar 5.75: CO--NH--CH(C═O)--CH(N--)--S-- 6.14 (dt, J=16 and 8) ppm:--C═CH--CH₂ --I E isomerism 6.8 to 7.4 (m):--S--CH═C(C═N--)--N═C(NH-trityl)-- and Ar--H of trityl 8.19 (d) :CO--CO--NH--CH(C═O)--CH(N--)--S--

STEP C:1-[3-[7β-[oxo-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-[oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridiniumiodide

3.93 g of the iodine derivative of Step B mixed with 6 g ofthieno-[2,3-b]-pyridine were stirred for one and a half hours at 20° C.and the mixture was precipitated from 400 ml of ether, filtered anddried under vacuum to obtain 4.12 g of the desired product with a Rf=0.1[eluant: dichloromethane-methanol (92-8)].

Analysis: C₄₉ H₄₀ IN₅ O₆ S₃ Calculated: %C 57.81 %H 3.96 %I 12.46 %N6.87 % 9.44 Found: 57.3 3.9 11.7 6.7 9.6

NMR analysis of the proton [CDCl₃, 300 MHz in ppm): 5.02 (d):CO--NH--CH(C═O)--CH--(N--)--S-- 5.27 (s): --CO--O--CH₂ --Ar 5.6 (dd):--CH═CH--CH₂ --N⁺ 5.74 (dt): CO--NH--CH(C═O)--CH(N--)--S-- 6.56 (d):--CH═CH--CH₂ --N⁺ E isomerism 7.3: Ar--H of the trityl 8.3:--S--CH═C(C═N--)--N═C(NH₂)-- 7.89 (d) : H in position 2 ofthieno-[2,3-b]-pyridinium 7.71 (d): H in position 3 ofthieno-[2,3-b]-pyridinium 8.8 (d): H in position 4 ofthieno-[2,3-b]-pyridinium 8.10 (m): H in position 5 ofthieno-[2,3-b]-pyridinium.

PREPARATION 11 [4-fluoro-(2,3-bis-hydroxy)-phenyl]-hydroxy acetic acid

51.2 g of 3-fluorocatechol and 36.8 g of glyoxylic acid were dissolvedat 20° C. in 160 ml of water and 34.8 g of sodium hydroxide in solutionin 400 ml of water were added to this solution cooled to 0° C. Themixture was heated for 4 hours at 46° C., then cooled to 0° C. and thepH was brought to 4.6 by the addition of concentrated hydrochloric acid.Extraction was carried out with ethyl ether (after evaporation 14.7 g ofthe starting 9-fluorocatechol were collected) and the aqueous phase wasacidified with concentrated hydrochloric acid until a pH of 1.8 wasobtained. Extraction was carried out with ethyl acetate and afterevaporation of the solvent, 47.7 g of the desired product were obtained(mixture of isomers, 2,3-bis-hydroxy-4-fluoro; 3,4-bis-hydroxy-5-fluoro;2-fluoro-3,4-bis-hydroxy) which was used as is in Step A of Example 16.

PREPARATION 12 3-bromo-4,5-bis-[(2-methoxyethoxy)-methoxy] benzaldehyde

Using the procedure of preparation 4, 5-bromo-vanillin was reacted toobtain the expected compound which was used in Example 15.

EXAMPLE 1

Internal salt of[6R-[3(E),6α,7β(Z)]]-1-[3-[7-[[2-amino-4-thiazolyl)[carboxy-(2-chloro-3,4-dihydroxy-phenyl]-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-quinolinium

STEP A: [2-chloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-hydroxyacetic acid

2.42 g of lithium chloride and 7.02 g of potassium hydroxide weredissolved in 30 ml of water at 0° C. and a solution of 10 g of2-chloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]benzaldehyde (synthesizedin Preparation 1), 2.8 ml of bromoform and 38 ml of dioxane were addedto this mixture. The mixture was stirred for 24 hours at 0° C. and thenanother 2.8 ml of bromoform were added. The mixture stood for 16 hoursand after dilution with 100 ml of water, the solution was washed withether, decanted, cooled to 0° C. and acidified until the pH was 2.5-3.Extraction was carried out with ether and the organic phase was washedwith water and dried. The solvent was driven off to collect 11.4 g ofthe desired product in the form of an oil with a Rf=0.1 [eluant:methylene chloride-methanol-acetic acid (89-10-1)].

Infrared analysis (CHCl₃): General absorption in the --OH region(acid+associated OH) 1726 cm⁻¹ complex: C═O of the acid function1598-1489 cm⁻¹ : aromatic nucleus

NMR analysis of the proton (CDCl₃ 250 MHz in ppm): 3.37 (1) (6H): --OCH₃3.57 (m) (4H), 3.81 (m) (2H) and 4.01 (m) (2H): O--CH₂ --O 5.25 (m) (4H)and 5.52 (sl) (1H): --O--CH₂ --O and Ar--CH--CO 7,.11 (sl) (2H): Ar--H.

STEP B; Diphenylmethyl[2-chloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-hydroxy acetate

11.4 g of the acid of Step A were dissolved at ambient temperature undernitrogen in 120 ml of dichloromethane and then 120 ml of a 0.3 molarsolution of diphenyl diazomethane in dichloromethane were added at 15°C. The mixture was stirred for 16 hours at ambient temperature and then30 ml of water were added, followed by decanting and acidifying with 309ml of acetic acid, washing with a saturated solution of sodiumbicarbonate, drying and evaporating the solvents. After chromatographyon silica, eluting with an ethyl acetate-hexane mixture (60-40), 8.1 gof the desired product were obtained.

Infrared analysis (CHCl₃): 3528 cm⁻¹ : non-phenolic --OH 1734 cm⁻¹ : C═Oof the ester function 1597, 1496, 487 cm⁻¹ : aromatic nucleus

NMR analysis of the proton (CDCl₃ 300 MHz in ppm): 3.36 (s): --OCH₃ 3.55(S) (4H), 3.82 (s) (2H) and 4.03 (s) (2H): --O--CH₂ --CH₂ --O 5.27 (s)and 5.29 (s): --O--CH₂ --O 5.67 (d after exchange): Ar--CH(C═O)--OH 6.88(s): CO--O--CHAr₂ 7.0 (masked) and 7.08 (d) : coupled Ar--H (ortho ofthe tetra-substituted ring 7.00 (2H), 7.18 (3H) and 7.30 (s) (5H): Ar--H

STEP C: Diphenylmethyl[2-chloro-3,4-bis-[(2-methoxy-ethoxy)methoxy]-phenyl]-phthalimidoxyacetate

2.47 g of N-hydroxy phthalimide and 7.55 g of triphenyl phosphine wereadded to a solution of 8.1 g of the ester of Step B in 90 ml oftetrahydrofuran and the mixture was cooled to 10° C. Then 3.88 ml ofdiethyl azodicarboxylate (DEAD) were poured into it and the mixture wasstirred for 16 hours. After concentration of the solvents andchromatography on silica, eluting with an ethyl acetate-hexane mixture(60-40), 6.27 g of the desired product were obtained in the form cf anoil with a Rf=0.25.

Infrared analysis (CHCl₃): 1739, 1755 (sh) and 1795 cm⁻¹ : C═O 1597,1489 cm⁻¹ : aromatic nucleus

NMR analysis of the proton (CDCl₃ 300 MHz in ppm): 3.33 and 3.37: --OCH₃3.54 (m) (4H), 3.82 (m) (2H) and 3.92 (m) (2H): O--CH₂ --CH₂ --O-- 5.22(AB sys.) and 5.30 (AB sys.): --O--CH₂ --O 6.50: Ar--CH(C═O)--O-- 6.93(s) ppm: CO--O--CH--Ar₂ 7.09 (d), 7.41 (d): coupled Ar--H (ortho of thetetrasubstituted ring) 7.44 (d) (4H): Ar--H of the phthalimido 7.05 to7.33 ppm: Ar--H aromatics

STEP D: Diphenylmethyl aminoxy(2-chloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl] acetate

6.27 g of the product of Step C were dissolved in 65 ml of ethanol andthe solution was cooled to 5° C. Then 0.47 ml of hydrazine hydrate wereadded and the mixture stood at 5° C. for half an hour and then wasreturned to ambient temperature for 2 hours. After filtration,evaporation of the solvent and chromatography on silica, eluting withethyl acetate, 3.64 g of the desired product were obtained in the formof an oil with a Rf=0.3.

Analysis: C₂₉ H₃₄ ClNO₉ Calculated: %C 60.46 %H 5.95 %N 2.43 Found: 60.16.1 2.6

Infrared analysis (CHCl₃): 3235 cm⁻¹ : --NH₂ 1738 cm⁻¹ : C═O of theester function 1598, 1572, 1490 cm⁻¹ : aromatic nucleus+NH₂

STEP E:[[[1-[2-chloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-[(triphenylmethyl)-amino]-thiazol-4-yl] acetic acid

0.69 g of the product of Step D and 0.496 g ofoxo-[2-[(triphenylmethyl)-amino]-thiazol-4-yl] acetic acid (BelgianPatent Applicaton No. 864,828) were stirred for 3 hours under nitrogenand at ambient temperature in the presence of 7 ml of methanol and thenthe solvent was eliminated. The residue was chromatographed on silica,eluting with a methylene chloride-methanol mixture (95-5) to obtain0.726 g of the expected product with a Rf=0.3 [eluant: CHCl₂ -MEOH(90-10)].

Analysis: C₅₃ H₅₀ ClN₃ O₁₁ S Calculated: %C 65.45 %H 5.18 %N 4.32 %S3.29 %Cl 3.64 Found: 63.7 5.1 4.2 3.2 3.1

STEP F: 4-methoxy-benzyl7β-[[[[1-[2-chloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylate

0.322 g of 4-methoxy-benzyl7β-amino-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylatehydrochloride (European Patent Application No. 0,333,154) and 0.72 g ofthe product of Step E were stirred in 10 ml of dichloromethane and themixture was cooled to 5° C. Then, 0.1803 g of1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC) were added, andthe mixture was stirred for half an hour. Then, the mixture was treatedwith 10 ml of potassium hydrogenophosphate in 10 ml of methylenechloride, followed by decanting, washing and drying and evaporating thesolvents to obtain 0.670 g of the expected product with a Rf=0.43[eluant: methylene chloride-ethyl acetate (80-20)].

STEP G: 4-methoxy-benzyl7β-[[[[1-[2-chloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[]-4,2,0]-oct-2-en-2-carboxylate

0.67 g of the product of Step F in 10 ml of acetone and 0.223 g ofsodium iodide were stirred for one hour at ambient temperature in thepresence of an iodine crystal. After elimination of the solvent, theresidue was taken up in methylene chloride and the organic phase waswashed and dried. The solvent was eliminated and crystallization wascarried out from isopropyl ether to obtain 0.579 g of the iodatedproduct with a Rf=0.27 [eluant: methylene chloride-methanol (90-10)].

STEP H: 1-[3-[7-[[[[1[2-chloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2[(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0][oct-2-en-3-yl]-2-propenyl]-quinoliniumiodide

0.572 g of the product of Step G were dissolved in 6 ml of methylenechloride and 0.234 g of quinoline were added. The mixture was stirredfor one hour and the solvent was evaporated. The residue was taken up inether, followed by crystallization and separation, and chromatographywas carried out on silica, eluting with a methylene chloride-methanolmixture (9-1) to obtain 0.235 g of the expected product with a Rf=0.27[eluant: methylene chloride-methanol (90-10)].

NMR analysis of the proton (CCDCl₃ 250 MHz; ppm): 3.31 to 3.34: --OCH₃3.73 (s): Ar--O--CH₂ 3.42 to 4.01: CH₂ --S and O--CH₂ --CH₂ --O 4.92(m): --CH(N--)--S-- 5.84 (m): --NH--CH--C-- 5.20 to 5.30: --O--CH₂ --Oand COO--CH₂ --Ar 5.93 to 6.15: ═C--CH₂ --N⁺ 6.40 to 6.55: ═CH--CH₂ -- Eisomerism and O--CH--Ar resolved 6.76: H in position 5 of the thiazolering 6.86 to 7.42: --CH--Ar₂, COO--CHAr₂, ═C--CH═CH-- E isomerism 8.05to 8.25 (3H), 8.37 (m) (1H), 8.92 (d (resolved)) (1H), and 10.4 (d):hydrogens of the quinoline ring 7.83 and 8.27: --CO--NH

STEP I: Internal salt of [6R-[3(E),6α,7β-(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)-[carboxy-(2-chloro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinoliniumisomer (R) and isomer (S)

A mixture of 0.235 g of the product of Step H and 5 ml oftrifluoroacetic acid containing 10% anisole was stirred for 90 minutesat ambient temperature. After the addition of ether, the mixture wassubjected to ultrasonics, followed by filtration, washing and drying for16 hours under vacuum at ambient temperature to obtain 0.118 g of thedesired internal salt.

Analysis: C₃₂ H₂₅ ClN₆ O₉ S₂ +1.5 C₂ HF₃ O₂ +0.5 HI; molecularweight=1014 Calculated: %C 43.81 %H 2.88 %N 8.28 %Cl 3.49 %S 6.32 %F8.42 %I 6.25 Found: 44.1 2.7 8.5 4.1 6.7 8.5 6.0

NMR analysis of the proton (DMSO 300 MHz in ppm): --S--CH₂--C(C═CH--)═C-- masked by the water of DMSO 5.15 (resolved d) ppm:CO--NH--CH(C═O)--CH--(N--)--S-- 5.72 to 5.89 (4H):CO--NH--CH(C═O)--CH(N--)--S--, Ar--CH(CO--O--)--O-- and --CH═CH--CH₂--N⁺ 6.38 (m) ppm: --CH═CH--CH₂ --N⁺ E isomerism 6.7 to 6.82:--S--CH═C(C═N--)--N═C(NH₂)-- and Ar--H of the catechol 6.98 ppm (dJ=15.5): --CH═CH--CH₂ --N⁺ E isomerism 7.30: NH₂ 8.06 (t) (1H), 8.25 (m)(2H), 8.54 (m) (2H) and 9.34 (d) (1H): Ar--H of the quinoline 9.29 (sl)and 9.94 (sl): mobile H's 9.47 (d) and 9.58 (d): Ar--H and--CO--NH--CH(C═O)--CH(N--)--S--

EXAMPLE 2 The internal salt of [6R-[3 (E),6α,7β-((Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)[carboxy-(3-cyano-4,5-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-quinolinium(R) or (S) or an (R+S) mixture

STEP A: [3-cyano-4,5-bis[-(2-methoxy-ethoxy)-methoxy]-phenyl]-hydroxyacetic acid

Using the procedure of Step A of Example 1, 6.2 g of the product of StepC of preparation 2, 4.4 g of potassium hydroxide, 3.15 g of lithiumbromide, 1.7 ml of bromoform and 15 ml were reacted and after stirringfor 48 hours at -5° C. 7 2 g of crude acid were obtained which, afterchromatography on silica eluting with a dichloromethane-methanol-aceticacid mixture (90-7-3), yielded 3.42 g of the desired product with aRf=0.3 [eluant: methylene chloride-methanol-acetic acid (91-07-3)].

Infrared analysis (CHCl₃): General absorption in the --OH region(acid+associated OH) 1721 cm⁻¹ max+1750 cm⁻¹ sh.: C═O of the acidfunction 2235 cm⁻¹ 1602-1586-1489 cm⁻¹ : aromatic nucleus

STEP B: Diphenylmethyl[3-cyano-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-hydroxy acetate

8.5 g of the acid of Step A were dissolved at ambient temperature undernitrogen in 100 ml of dichloromethane and then 75 ml of a 0.3 molarsolution of diphenyl diazomethane in ether were added at 15° C. Themixture was stirred for 16 hours at ambient temperature and then 30 mlof water were added, followed by decanting and acidifying with 30 ml ofacetic acid, washing with a saturated solution of sodium bicarbonate,drying and evaporating the solvents. After chromatography on silica andeluting with an ethyl acetate-hexane mixture (50-50), 4.2 g of thedesired product with a Rf=0.3 were obtained.

Infrared analysis (CHCl₃): 3525 cm⁻¹ : non-phenolic --OH 2235 cm⁻¹ : C═N1732 and 1750 cm⁻¹ : C═O of the ester function 1600, 1585, 1495, 1490cm⁻¹ : aromatic nucleus

NMR analysis of the proton (CDCl₃ 300 MHz in ppm): 3.32 to 3.47: --OCH₃3.58 and 3.72: O--CH₂ --CH₂ --O 5.15 to 5.40: --OCH₂ --O andAr--CH(C═O)--OH 6.89 (s): CO--O--CHAr₂ 7.24 to 7.50: Ar--H

STEP C: Diphenylmethyl[3-Cyano-4,5-bis-[(2-methoxy-ethoxy)-methoxy-phenyl]-phthalimidoxyacetate

0.134 g of N-hydroxy phthalimide and 0.409 g of triphenyl phosphine wereadded to a solution of 0.430 g of the ester of Step B in 10 ml oftetrahydrofuran and the mixture was cooled to -10° C. Then, 0.21 ml ofdiethyl azodicarboxylate (DEAD) was poured in and the mixture wasstirred for 16 hours. After concentrating the solvents andchromatography on silica eluting with a dichloromethane-acetone mixture(95-5), 0.2 g of the desired product in the form of an oil and with aRf=0.25 [eluant: dichloromethane-acetone (97-3)] were obtained.

Infrared analysis (CHCl₃): 1792 (m), 1775 (sh) 1760 (sh) and 1738 (max)cm⁻¹ : C═O 2230 cm⁻¹ : C═N 1604, 1586, 1490 cm⁻¹ : aromatic nucleus

STEP D: Diphenylmethyl-aminoxy[3-cyano-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl] acetate

2.7 g of the product of Step C were dissolved under nitrogen in 80 ml ofethanol and the solution was cooled to -2° C. Then, 0.20 ml of hydrazinehydrate were added and the mixture was held at -2° C. for half an hour,then returned to ambient temperature for one hour. After filtration,evaporation of the solvent and chromatography on silica eluting with anethyl acetate-hexane mixture (7-3) yielded 1.8 g of the desired productin the form of an oil with a Rf=0.25.

Analysis: C₃₀ H₃₄ N₂ O₉ Calculated: %C 63.53 %H 6.04 %N 4.94 Found: 63.36.4 4.6

Infrared analysis (CHCl₃): 3335 cm⁻¹ : O--NH₂ 2230 cm⁻¹ : C═N 1748 cm⁻¹: C═O of the ester function 1600, 1588, 1488 cm⁻¹ : aromatic nucleus+NH₂

STEP E:[[[1-[3-cyano-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-[(triphenylmethyl)-amino]-thiazolyl] acetic acid

0.650 g of the product of Step D and 0.428 g ofoxo-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetic acid (BelgiumPatent Application No. 864,828) were stirred for 2 hours under nitrogenat ambient temperature in the presence of 6 ml of methanol. The solventwas eliminated and the residue was taken up in ether. Filtration wascarried out and the filtrate was chromatographed on silica, eluting witha methylene chloride-methanol mixture (95-5) to obtain 0.841 g in totalof the expected product melting at 158° C.

Infrared analysis (CHCl₃): 3402 cm⁻¹ : ═C--NH General absorption OH/NH2235 cm⁻¹ : C═N 1755 (sh), 1740 (max) and 1717 (sh) cm⁻¹ : C═O 1587,1531 1509 and 1490 cm⁻¹ : aromatic, heterocycle, conjugated system

NMR analysis of the proton (in ppm): 3.36 (s) and 3.43 (s): --OCH₃ 3.55to 3.90 (m) (6H) and 4.05 (m) (2H): O--CH₂ --CH₂ --O 5.03 (d), 5.12 (d)and 5.33 (d): --O--CH₂ --O 5.85 (s): Ar--CH(C═O)--O-- 6.68 (s):CO--O--CHAr₂, 6.87 (s): --S--CH═C(C═N)--N 7.10 to 7.36 (massive) (27H),7.67 (d) (1H): Ar--H

STEP F: 4-methoxy benzyl7β-[[[[1-[3-cyano-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino] [2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylate

0.160 g of 4-methoxy-benzyl7β-amino-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylatehydrochloride (European Patent Application No. 0,333,154) and 0.36 g ofthe product of Step E in 5 ml of dichloromethane were stirred and cooledto 5° C. Then, 0.0893 g of EDC were added and the mixture was stirredfor 15 minutes, then treated with 15 ml of potassium hydrogenophosphatein 8 ml of dichloromethane, decanted, washed and dried. The solventswere evaporated and after chromatography on silica, eluting with adichloromethane-ethyl acetate mixture (8-2) yielded. 0.349 g of theexpected product with a Rf=0.4 [eluant: dichloromethane-ethyl acetate(8-2)].

STEP G: 4-methoxy-benzyl7β-[[[[1-[3-cyano-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylate

0.573 g of the product of Step F in 7 ml of actone and 0.192 g of sodiumiodide wre stirred for one hour at ambient temperature in the presenceof an iodine crystal. After elimination of the solvent, the residue wastaken up in dichloromethane and the organic phase was washed and dried.The solvent was eliminated and the residue was crystallized fromisopropyl ether to collect 0.463 g of the iodated product with a Rf=0.30[eluant: dichloromethane methanol (9-2)].

STEP H:1-[3-[7-β-[[[[1-[3-cyano-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0][oct-2-en-3-yl]-2-propenyl]-quinolinium iodide

0.463 g of the product of Step G were dissolved in 4 ml ofdichloromethane and 0.191 g of quinoline was added. The mixture wasstirred for one hour, and the solvent was evaporated. The residue wastaken up in ether and crystallized and separation was carried outfollowed by chromatography on silica. Elution with adichloromethane-methanol mixture (97-3) yielded. 0.241 g of the expectedproduct with a Rf=0.27.

NMR analysis of the proton (CDCl₃ 400 MHz in ppm): 3.25 (s), 3.27 (s)and 3.34: --OCH₃ 3.26 to 4.04: CH₂ --S and O--CH₂ --CH₂ --O 3.98 (s)Ar--O--CH₃ 4.90 to 5.08 and 5.15 to 5.40: --CH(N--)--S--, ═C--CH₂ --N⁺,--O--CH₂ O and COO--CH₂ --Ar 5.75 to 6.05: N--CH(C═O)--CH--(N--)---- and--O--CH(C═O)--Ar 6.38 (m) and 6.56 (m): ═CH--CH-- E isomerism 6.73 (m):L--S--CH--C(C═N)--N 6.80 to 7.50: trityl's, COO--CHAr₂, 7.9 to 8.56 (5H),8.56 (d) and 8.87 (d) resolved in (1H), 10.27 (d) and 10.83 (d):hydrogens of the quinoline ring and --NH--

STEP I: Internal salt of [6R-[3-(E),6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)[carboxy-(3-cyano-4,5-dihyroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-quinoliniumisomer (R) and isomer (S)

A mixture of 0.241 g of the product of Step H and 5 ml oftrifluoroacetic acid containing 10% anisole was stirred for one and ahalf hours at ambient temperature. After the addition of ether,crystallizing, filtering, washing and drying for 16 hours under vacuumat ambient temperature, 0.128 g of the sought internal salt wereobtained.

Analysis: C₃₃ H₂₅ N₇ O₉ S₂ +1.4 C₂ HF₃ O₂ +0.4 HI Calculated: %C 45.8 %H2.87 %N 10.43 %S 6.83 %F 8.5 %I 5.4 Found: 44.1 2.7 8.5 7.0 8.0 4.1

NMR analysis of the proton (DMSO 300 MHz in ppm): 3.53 (d) and 3.74 (d):--S--CH₂ --C(C═CH--)═C-- 5.14 (resolved d) ppm:CO--NH--CH--(C═O)--CH--(N--)--S-- 5.40 (s): Ar--CH(CO--O--)--O-- 5.76(m) CO--NH--CH--(C═O)--CH(N--)--S-- to 5.89 (m): --CH═CH--CH₂ --N⁺, 6.34(m) ppm: --CH═CH--CH₂ --N⁺ E isomerism 6.76 (s) and 6.79 (s):--S--CH═C(C═N--)--N═C(NH₂)-- 6.98 ppm (d J=16): --CH═CH--CH₂ --N⁺ Eisomerism 7.11 to 7.15 (m) (2H): Ar--H 7.30 (m) and 10.38 (m): mobileH's 8.06 (t) (1H), 8.26 (m) (2H), 8.53 (m) (2H), 9.33 (d) and 9.58 (d):Ar--H 9.60 (d) and 9.65 (d): --CO--NH--CH(C═O)--CH(N--)--S--

EXAMPLE 3 The internal salt of[6R-[3(E),6α,7β-(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)[carboxy-(3-fluoro-4,5-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-quinolinium(R) or (S) or an (R+S) mixture

STEP A:[3-fluoro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-hydroxy-aceticacid

0.662 g of lithium bromide and 3.6 g of potassium hydroxide weredissolved in 13 ml of water at 0° C. and a solution of 5.5 g of3-fluoro-4,5-bis-[(2-methoxy-ethoxy)-methoxy benzaldehyde (synthesizedin Preparation 3), 2.85 ml of bromoform and 13 ml of dioxane were addedto this mixture. The mixture stood with stirring for 24 hours at 0° C.and then another 2.85 ml of bromoform were added. The mixture stood forone night and after dilution in water and washing with ether, decantingtook place, followed by cooling to 0° C., acidifying until the pit was2.5-3 and extracting with ether. The organic phase was washed withwater, dried and the solvent was evaporated to obtain 5.3 g of thedesired product in the form of an oil.

Infrared analysis (CHCl₃): 3600 cm⁻¹ : --OH region (acid+associated OH)1715 cm⁻¹ complex: C═O of the acid function 1616, 1595 and 1510 cm⁻¹ :aromatic nucleus

STEP B: Diphenylmethyl[3-fluoro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-hydroxy-acetate

5.3 g of the acid of Step A were dissolved in 66 ml of dichloromethaneand then 46 ml of a solution of diphenyl diazomethane at 6.5 g in etherwere added at 15° C. The mixture was stirred for 16 hours at ambienttemperature and then water was added, followed by decanting andacidifying with acetic acid. Washing with a saturated solution of sodiumbicarbonate, drying and evaporating the solvents yielded afterchromatography on silica and eluting with an ethyl acetate-hexanemixture (50-50) 4.0 g of the desired product with a Rf=0.17.

Infrared analysis (CHCl₃): 3520 cm⁻¹ : non-phenolic --OH 1735 cm⁻¹ : C═Oof the ester function 1615, 1595 and 1509 cm⁻¹ : aromatic nucleus

NMR analysis of the proton (CDCl₃ 2500 MHz in ppm): 3.33 (s) and 3.37(s): --OCH₃ 3.46 (m), 3.57 (m), 3.78 (m) and 3.98 (m): O--CH₂ --CH₂ --O5.19 to 5.30: --O--CH₃ --O and Ar--CH(C═O--O)--O-- 6.87 (s):CO--O--CHAr₂ 6.87 (m) (1H), 6.97 (m) (2H), 7.07 (m) (1H), 7.21 (m) (3H)and 7.32 (m) (5H): Ar--H

STEP C: Diphenylmethyl[3-fluoro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-phthalimidoxy-acetate

0.77 g of N-hydroxy phthalimide and 2.42 g of triphenyl phosphine wereadded to a solution of 2.6 g of the ester of Step B in 28 ml oftetrahydrofuran, and after cooling to -10° C. 14 ml of diethylazodicarboxylate (DEAD) were added dropwise into the resultant mixture.The mixture was stirred at 0° C. for one and a half hours. Afterconcentration of the solvents and chromatography on silica, elution witha dichloromethane-acetone (95-5) mixture yielded 2.56 g of the desiredproduct in the form of an oil with Rf=0.6 [eluant:dichloromethane-acetone (85-15)].

Infrared analysis (CHCl₃): 794, 1752 and 1738 (max) cm⁻¹ : C═O

NMR analysis of the proton (CDCl₃ 250 MHz in ppm): 3.34 (s) and 3.33(s): --OCH₃ 3.48 (m) (2H), 3.56 (m) (2H), 3.77 (m) (2H) and 3.96 (m)(2H): O--CH₂ --CH₂ --O 5.22 (m) (4H): --O--CH₂ --O 5.92 (s):Ar--CH(C═O--O)--O-- 6.92 (s): CO--O--CHAr₂ 7.00 to 7.35 (m): Ar--H 7.75(m) (4H): Ar--H of the phthalimide

STEP D: Diphenylmethylaminoxy-[3-fluoro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-acetate

2.4 g of the product of Step C were dissolved under nitrogen in 25 ml ofethanol and the mixture was cooled to -5° C. Then, 0.38 ml of hydrazinehydrate were added and the mixture was held at -5° C. for two hours.After filtration, the solvent was evaporated and the residue waschromatographed on silica, eluting with a mixture of ethylacetate-hexane (7-3) to obtain 1.67 g of the desired product in the formof an oil with a Rf=0.3.

Infrared analysis (CHCl₃): 3340 cm⁻¹ : O--NH₂ 1747 cm⁻¹ : C═O of theester function 1616, 1596, 1581, 1508 and 1497 cm⁻¹ : aromaticnucleus+NH₂

NMR analysis of the proton (CDCl₃ 300 MHz in ppm): 3.34 and 3.36: --OCH₃3.48, 3.56, 3.77 and 3.97: O--CH₂ --CH₂ --O 5.17 (s):Ar--CH(C═O--O)--O-- 5.20 and 5.21: --O--CH₂ --O 5.79 (s): O--NH₂ 6.82(dd): Ar--H in ortho position of F 6.91 (s): CO--O--CHAr₂ 7.02: Ar--H inpara position of F 7.05 to 7.40: Ar--H

STEP E:[[[1-[3-fluoro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-aceticacid

0.640 g of the product of Step D and and 0.474 g ofoxo-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetic acid (BelgianPatent Application No. 864,828) were stirred for 4 and a half hoursunder nitrogen and at ambient temperature in the presence of 20 ml ofmethanol. Then, the solvent was eliminated, and the residue waschromatographed on silica, eluting with a dichloromethane-methanol(95-5) mixture to obtain 0.612 g of the expected product with a Rf=0.35[eluant: dichloromethane-methanol (9-1)].

Infrared analysis (CHCl₃): 3400 cm⁻¹ : ═C--NH 1755 (shoulder), 1736(max) cm⁻¹ : C═O 1695, 1527, 1509 and 1496 cm⁻¹ : aromatic, heterocycle,1635 cm⁻¹ : C═O

NMR analysis of the proton (CDCl₃ in ppm): 3.09 (s) and 3.22 (s): --OCH₃3.30 (m), 3.55 (m), 3.60 (m), 3.92 (m),: O--CH₂ --CH₂ --O 5.15 (s), 5.10(d) and 5.20 (d): --O--CH₂ --O 5.81 (s): Ar--CH(C═O)--O-- 6.56 (s):CO--O--CHAr₂, 6.74 (s): --S--CH═C(C═N)--N 7.10 to 7.33 (m): Ar--H

STEP F: 4-methoxy-benzyl7β-[[[[[1-[3-fluoro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-2-(triphenylmethyl]-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylate

0.289 g of 4-methoxy-benzyl 7β-amino-3-[(Z)-3-chloro-1propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylatehydrochloride (European Patent Application No. 0,333,154), and 0.641 gof the product of Step E in 6 ml of dichloromethane were stirred andcooled to 5° C. Then 0.160 g of EDC was added and the mixture wasstirred for half an hour. Then, the mixture was treated with potassiumhydrogen phosphate in dichloromethane, followed by decanting, washing,drying and evaporating the solvents. After chromatographing on silicaeluting with a dichloromethane-ethyl acetate (8-2) mixture, 0.678 g ofthe expected product with a Rf=0.4 [eluant: dichloromethane-ethylacetate (8-2)] were obtained.

STEP G: 4-methoxy-benzyl7β-[[[[[1-[3-fluoro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-iodo-propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylate

0.678 g of the product of Step F in 7 ml of acetone and 0.228 g ofsodium iodide were stirred for one hour at ambient temperation in thepresence of an iodine crystal. After eliminating of the solvent, theresidue was taken up in dichloromethane and the organic phase was washedand dried. The solvent was eliminated and the residue was separated toobtain 0.501 g of the iodated product with a Rf=0.2 [eluant:dichloromethane -methanol (97-3)].

STEP H:1-[3-[7β-[[[[[1-[3-fluoro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-quinolinium iodide.

0.500 g of the product of Step G dissolved in 2 ml of dichloromethaneand 0.226 ml of quinoline were added and the solvent was concentrated.The mixture was stirred for one hour at ambient temperature and 2 ml ofdichloromethane were added. Then precipitation was carried out withether and chromatography took place on silica eluting with adichloromethane-methanol (97-3) mixture to obtain 0.220 g of theexpected product with a Rf=0.20.

STEP I: Internal salt of [6R-[3(E), 6α,7β-(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)-[[carboxy-(3-fluoro-4,5-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-8-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-quinolinium(R) isomer and (S) isomer

A mixture of 0.220 g of the product of Step H and 5 ml oftrifluoroacetic acid containing 10% anisole was stirred at ambienttemperature for one and a half hours. After 15 ml of ether were added,the precipitate was washed and dried to obtain 0.0994 g of the desiredinternal salt.

Analysis: C₃₂ H₂₅ FN₆ O₉ S₂ +1.2 C₂ HF₃ O₂ +0.5 HI Calculated: %C 44.8%H 2.89 %n 9.12 %S 6.95 %F 9.48 %I 6.88 Found: 44.7 2.8 8.8 6.6 9.1 6.6

NMR analysis of the proton (DMSO 300 MHz in ppm): 3.5 and 3.8: (maskedby the water of the solvent) 5.14 (d resolved) ppm:CO--NH--CH(C═O)--CH--(N--)--S-- 5.34 (s resolved): Ar--CH(CO--O--)--O--5.77 (dd resolved d resolved): CO--NH--CH(C═O)--CH(N--)--S-- 5.80 to6.0: --CH═CH--CH₂ --N⁺, 6.37 (m): --CH═CH--CH₂ --N⁺ E isomerism 6.7 to6.8: --S--CH═C(C═N--)--N═C(NH₂)-- and Ar--H in ortho and para positionof F. 6.98 ppm (d resolved): --CH═CH--CH₂ --N⁺ E isomerism 8.07 (t),8.29 (t): H in positions 6 and 7 of the quinolinium 8.24 (dd): H inposition 3 of the quinolinium 8.53: H in positions 5 and 8 of thequinolinium 9.34 (d): H in position 4 of the quinolinium 9.58 (d): H inposition 2 of the quinolinium 7.31-9.19 and 9.5 to 9.7: mobile H's

EXAMPLE 4 The internal salt of[(±)(cis)(Z)]7-[3-[7-[[(2-amino-4-thiazolyl)-[[carboxy-(3-chloro-4,5-dihydroxy-phenyl]-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]oct.2-en-3-yl]2 (E)-propenyl]-thieno-[2,3-b]-pyridinium (R) or (S) or an (R+S) mixture

STEP A: [3-chloro-4,5-bis-[(2-methoxy-ethoxy]-methoxy]phenyl]-hydroxyacetic acid

3.34 g of lithium chloride and 9.64 g of potassium hydroxide weredissolved in 36 ml of water at 0° C. and a solution of 13.77 g of3-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy benzaldehyde (synthesizedin Preparation 3). 3.74 ml of bromoform and 34 ml of dioxane were addedto this mixture. The mixture was stirred for 24 hours at 0° C. and thenanother 3.74 ml of bromoform were added. The resultant mixture wasstirred for 16 hours and after dilution in 100 ml of water and washingwith ether. Decanting took place, followed by cooling to 0° C.,acidifying to a pH of 2.5-3 and extracting with ether. The organic phasewas washed with water, dried and the solvent was evaporated to obtain13.95 g of the desired product in the form of a yellow oil.

Infrared analysis (CHCl₃): 1700 (max) and 1730 (shoulder) cm⁻¹ : C═O1599, 1578, 1489 cm⁻¹ : aromatic nucleus

NMR analysis of the proton (CDCl₃ 250 MHz in ppm): 3.38 (m) (6H): --OCH₃5.09 to 5.35 (m): --O--CH₂ --O and Ar--CH(C═O)--O 7.05 to 7.78 ppm (m)(2H): Ar--H

STEP B: Diphenylmethyl[3-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-hydroxy acetate

13.95 g of the acid of Step A were dissolved in 150 ml of ether atambient temperature and under nitrogen and then 150 ml of a 0.3 molarsolution of diphenyl-diazomethane in dichloromethane were added at 15°C. The mixture was stirred for 16 hours at ambient temperature and then,30 ml of water were added, followed by decanting and acidifying with 30ml of acetic acid. Washing took place agains with a saturated solutionof sodium bicarbonate, followed drying and evaporating the solvents.After chromatographingon silica eluting with a dichloromethane,-methanol(99-1) mixture, 10 g of the desired product were obtained.

Infrared analysis (CHCl₃): 3535 cm⁻¹ : non-phenolic --OH 1738 cm⁻¹ : C═Oof the ester function 1600, 1580, 1489 cm⁻¹ : aromatic nucleus

NMR analysis of the proton (CDCl₃ 250 MHz in ppm): 3.59 (m) and 3.47 (m)(4H), 3.75 (m) (2H) and 4.04 (m) (2H): O--CH₂ --CH₂ --O 3.38, 3.33 and3.25 (m) (6H): --OCH₃ 5.02 to 5.30 (m): O--CH₂ --O and Ar--CH(C═O)--O6.8 to 7.35 (m): Ar--H

STEP C: Diphenylmethyl[3-chloro-4,5bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-phthalimidoxyacetate

1 g of N-hydroxy phthalimide and 1.54 g of triphenyl phosphine wereadded to a solution of 1 g of the ester of Step B in 35 ml oftetrahydrofuran, followed by cooling to 10° C. Then, 1.58 g of diethylazodicarboxylate (DEAD) were added dropwise and the mixture was stirredfor 16 hours. After concentration of the solvents, chromatography onsilica and eluting with a dichloromethanemethanol (99-1) mixtureyielded. 3.09 g of the desired product in the form of a colorless oil(Rf=0.3).

Infrared analysis (CHCl₃): 1738, 1755 (shoulder) and 1795 cm⁻¹ : C═O1600, 1578, 1488 cm⁻¹ : aromatic nucleus

NMR analysis of the proton (CDC₃ 250 MHz in ppm): 3.34 (s), and 3.36 (s): --OCH₃ 3.49 (m) (2H),3.57 (m) (2H), 3.77 (m) (2H) and 4.02 (in) (2H)ppm: O--CH₂ --CH₂ --O 5.22 (s) and 5.27 (s) ppm: --O--CH₂ --O 5.91 (s)and 5.92 (s) ppm: Ar--CH(C═O)--O 6.92 (s) ppm: CO--O--CH--Ar₂ 7.75 ppm(m) (4H): Ar--H of the phthalimido 7.11 (m) and 7.21 to 7.33 ppm: theother aromatic H's

STEP D: Diphenylmethyl aminoxy[3-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl] acetate

3 g of the product of Step C were dissolved under a nitrogen atomospherein 40 ml of ethanol and the mixture was cooled to 5° C. Then, 0.224 mlof hydrazine hydrate were added and the mixture was stirred at 5° C. forhalf an hour, then returned to ambient temperature for 2 hours. Afterfiltration and evaporation of the solvent, the desired product wasobtained in the form of an oil with a Rf=0.3 [eluant: acetone-cyclohexane (3-7)].

Infrared analysis (CHCl₃): 3330 cm⁻¹ : --NH₂ 1745 cm⁻¹ : C═O 1600, 1578,1488 cm⁻¹ : aromatic nucleus+NH₂

NMR analysis of the proton (CDCl₃ 250 MHz in ppm): 3.34 (s) and 3.38(s): --OCH₃ 3 48 (m), 3.58 (m), 3.76 (m) and 4.02 (m): O--CH₂ --CH₂ --O5.17: Ar--CH(C═O)--O 5.80: mobile NH₂ 6.91 (s): CO--O--CH--Ar₂ 7.10 (m)(4H) and 7.21 to 7.33 (8H): Ar--H

STEP E:7-[3-[7β-[[[[[1-[3-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-[oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridinium iodide

0.441 g of the-product of Step D, 24 ml of methanol and 145 ml ofp-toluene sulfonic acid were mixed under a nitrogen atmosphere for 5minutes and a solution of 0.65 ml of1-[3-[7β-[oxo-[2-[(triphenylmethyl)-amino]-thizol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-[oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridiniumiodide (preparation 10) were added. Then, the mixture was stirred for 16hours and after evaporation of the solvent, the residue was taken up inether. The precipitate was filtered, washed and dried to obtain 0.730 gof the desired product with a melting point of 135° C. (gum) and aRf=0.3 [eluant: dichloromethane-methanol (9-1)].

STEP F: The internal salt of [(±)(cis(Z)]7-[3-[7-[[(2-amino-4-thiazolyl)-[carboxy-(3-chloro-4,5-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2(E)-propenyl]-thieno-[2,3-b]-pyridinium(R) or (S) or an (R+S) mixture

A solution of 31 ml of trifluoroacetic acid in 8.5 ml of dichloromethanewas poured at 0° C. into a mixture at 0° C. of 0.69 ml of the product ofStep E, 17 ml of dichloromethylene and 3 ml of anisole and the mixturewas stirred at this temperature for one hour. The solvents wereeliminated, followed by crystallizing, filtering, washing and drying,chromatography and elution with an acetonitrile-water (1-1) mixtureyielded 0.22 g of the desired product.

NMR analysis of the proton (DMSO 300 MHz in ppm): 3.19: C═C--CH₂ --S--5.01 (d) and 5.07 (d): CO--NH--CH (C═O)--CH--(N--)--S-- 5.12 (s) and5.17 (s): Ar--CH(CO--O--)--O-- 5.52 (1): --CH═CH--CH₂ --N⁺, 5.60:CO--NH--CH(C═O)--CH--(N--)--S-- (cis/H in position 6) 5.87 (m):--CH═CH--CH₂ --N⁺ E isomerism 6.78 to 6.86: --S--CHC(C═N--)--N═C(NH₂)--and Ar--H in ortho and para position of the Cl 7.21 and 7.41: --NH₂ 7.87(d): H in position 3 of the thieno-[2,3-b]-pyridinium 8.10 (1): H inposition 5 of the thieno-[2,3-b]-pyridinium 8.26 (d): H in position 2 ofthe thieno-[2,3-b]-pyridinium 9.03 (1): H in position 4 of thethieno-[2,3-b]-pyridinium 9.23: (1) H in position 6 of thethieno-[2,3-b]-pyridinium 9.74 (d): CO--NH--CH(C═O)--CH(N--)--S--

Using the procedure of Example 4, the products of preparations 1 to 12were reacted to obtain the following compounds:

EXAMPLE 5 The internal salt of[[6R-[3(E),6α,7β(Z)]]7-[3-[7-[[(2-amino-4-thiazolyl)-[carboxy-(3,4-dihydroxy-5-nitro-phenyl)-methoxy]imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridinium(R) or (S) or an (R+S) mixture NMR

NMR analysis of the proton 9DMSO 300 mHz in ppm): 3.49 to 3.9 (m)(C═C--CH₂ --S-- 3.14 (d) and 5.18 (d): CO--NH--CH(C═O)--CH--(N--)--S--5.47 (s), 5.50 (s), 5.60 (s), 5.63 (s): Ar--CH--(CO--O--)--O-- 6.67 (d):--CH═CH--CH₂ --N⁺, 5.77 (m): CO--NH--CH(C═O)--CH--(N--)--S-- 6.29 (m):--CH═CH--CH₂ --N⁺ 6.80 (s), 6.83 (s), 7.64 (s) and 7.66 (s):--S--CH═C(C═N--)--N═C(NH₂)-- 7.42 (d) and 7.47 (d): Ar--H in orthoposition of the nitro 7.1 to 7.2 (m): --CH═CH--CH₂ --N⁺ and Ar--H inpara position of the nitro 7.89 (d): H in position 3 of thethieno-[2,3-b]-pyridinium 8.15 (dd): H in position 5 of thethieno-[2,3-b]-pyridinium 8,.29 (d): H in position 2 of thethieno-[2,3-b]-pyridinium 8.09 (d): H in position 4 of thethieno-[2,3-b]-pyridinium 9.23 (d): H in position 6 of thethieno-[2,3-b]-pyridinium 9.54 (d res.), 9.65 (d) and 9.69 (d):CO--NH--CH--(C═O)--CH--(N--)--S-- 10.42 (m): mobile H's

EXAMPLE 6 The internal salt of [(±)(cis)(Z)]7-[3-[7-[[(2-amino-4-thiazolyl)-[carboxy-(3,4-dihydroxy-5-iodo-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-(E)-propenyl]-thieno-[2,3-b]-pyridinium(R) or (S) or an (R+S) mixture

Analysis: C₃₀ H₂₃ IN₆ O₉ S₃ +1 C₂ HF₃ O₂ +1 APTS Calculated: %C 41.78 %H2.85 %N 7.5 %S 11.43 %I 11.3 Found: 4 6.6 2.8 7.8 12.0 10.9

NMR analysis of the proton (DMSO 300 MHz in ppm): 3.70: C═C--CH₂ --S--5.11 (s) and 5.17 (s) (1H): CO--NH--CH(C═O)--CH--(N--)--S-- 5.29 (s) and5.32 (s): Ar--CH(CO--O--)--O-- 5.67 (d): --CH═CH--CH₂ --N⁺, 5.75 (m):CO--NH--CH(C═O)--CH(N--)--S-- 6.29: --CH═CH--CH₂ --N⁺ E isomerism 6.77(resolved) (1H): --S--CH═C(C═N--)--N═C(NH₂)-- 6.90 (2H): Ar--H in orthoand para position of I 7.89 (d): H in position 3 of thethieno-[2,3,-b]-pyridinium 8.15 (dd): H in position 5 of thethieno-[2,3-b]-pyridinium 8.29 (d): H in position 2 of thethieno-[2,3-b]-pyridinium 9.09 (d): H in position 4 of thethieno-[2,3-b]-pyridinium 9.13 (d): H in position 6 of thethieno-[2,3-b]-pyridinium 9.37 (sl): CO--NH--CH(C═O)--CH(N--)--S--

EXAMPLE 7 The internal salt of [(±)(cis)(Z)]7-[3-[7-[[(2-amino-4-thiazolyl)-[crboxy-(3,4,5-trihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2(E)-propenyl]-thieno-[2,3-b]-pyridinium(R) or (S) or an (R+S) mixture

NMR analysis of the proton (DMSO 300 MHz in ppm): 5.15 (d) and 5.17 (d)(1H): CO--NH--CH(C═O)--CH--(N--)--S--[2/5 (R/S) 3/5] 5.22 and 5.34 (2H):Ar--CH(CO--O)--O-- 5.67 (d): --CH═CH--CH₂ --N⁺, 5.76 (m), 6.20 to 6.49(m): CO--NH--CH(C═O)--CH(N--)--S--, CH═CH--CH₂ --N⁺ and Ar--H of thetriphenol 6.75, 6.77, 6.87 and 6.90 (1H): --S--CH═C(C═N--)--N═C(NH₂)--7.74 (d): H in position 5 of the thieno-[2,3-b]-pyridinium 7.89 (d) and8.28 (d): H in positoins 4 and 3 of the thieno-[2,3-b]-pyridinium 8.10to 8.27, 9.09 and 9.23: H in positions 2 and 6 of the thieno-[2,3-b]-pyridinium 9.6 to 9.85: CO--NH--CH(C═O)--CH(N--)--S--

EXAMPLE 8

The internal salt of [(+) (cis)(Z)]7-[3-[7-[[(2-amino-4-thiazolyl)-[carboxy-(2-chloro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2(E)-propenyl]-thieno-[2,3-b]-pyridinium(R) or (S) or an (R+S) mixture

Analysis: C₃₀ H₂₃ IN₆ O₉ S₃ +2 APTS Found: %C 46.8 %H 2.55 %N 8.53 %S9.76 %Cl 3.59

NMR analysis of the proton (DMSO 300 MHz in ppm): 3.5 to 3.9 (m):C═C--CH₂ --S-- 5.17 (m) (1H): CO--NH--CH(C═O)--CH--(N--)--S-- 5.67 (dl):--CH═CH--CH₂ --N⁺, 5.70 to 5.90 (2H): CO--NH--CH(C═O)--CH(N--)--S-- +other H 6.33 (m): --CH═CH--CH₂ --N⁺ E isomerism 6.79 and 6.96 (m) (4H):4H 7.89 (d) and 8.29 (d): H in positions 2 and 3 of the thieno-[2,3-b]-pyridinium 8.14 (m): H in position 5 of the thieno-[2,3-b]-pyridinium9.08 (d): H in position 4 of the thieno-[2,3-b]-pyridinium 9.26 (d): Hin position 6 of the thieno-[2,3-b]-pyridinium

EXAMPLE 9 The internal salt of [[6R-[3 (E),6α, 7β(Z)]]7-[3-[7-[[(2-amino-4-thiazolyl)-[carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridinium(R) or (S) or an (R+S) mixture

NMR analysis of the proton (DMSO 300 MHz in ppm): 5.20: Ar--H in orthoposition of the Cl 5.79: Ar--CH(CO--O--)--O-- 5.78 (m): --CH═CH--CH₂--N⁺, 6.31: --CH═CH--CH₂ --N⁺ 7.88: H in position 3 of thethieno-[2,3-b]-pyridinium 8.15 (m): H in position 5 of thethieno-[2,3-b]-pyridinium 8.98 (m): H in position 2 of thethieno-[2,3-b]-pyridinium 9.09 (d): H in position 4 of thethieno-[2,3-b]-pyridinium 9.12 (d): H in position 6 of thethieno-[2,3-b]-pyridinium

EXAMPLE 10 The internal salt of [[6R-[3(E),6α,7β(Z)]]7-[3-[7-[[(2-amino-4-thiazolyl)-[carboxy-(3-cyano-4,5-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridinium(R) or (S) or an (R+S) mixture

NMR analysis of the proton (DMSO 300M MHz in ppm): 3.19: C═C--CH₂ --S--5.15 (D) and 5.20 (d): CO--NH--CH(C═O)--CH--(N--)--S-- 5.40 (s):Ar--CH(CO--O--)--O-- 5.67 (d): --CH═CH--CH₂ --N⁺, 5.81 (m):CO--NH--CH(C═O)--CH(N--)--S-- 6.67 (S): --S--CH═C(C═N--)--N═C(NH₂)--7.10 to 7.20 (m) (3H): Ar--H and CH═ 7.34 (m), 10.27 to 10.42 (m):mobile H's 7.89 (d): H in position 3 of the thieno-[2,3-b]-pyridinium8.15 (dd): H in position 5 of the thieno-[2,3-]-pyridinium 8.28 (d): Hin position 2 of the thieno-[2,3-b]-pyridinium 9.09 (d): H in position 4of the thieno-[2,3-b]-pyridinium 9.23 (d): H inposition 6 of thethieno-[2,3-b]-pyridinium 9.52 (d) and 9.62 (d):CO--NH--CH(C═O)--CH--(N--)--S--

EXAMPLE 11 The internal salt of[[6R-[3(E),6α,7β(Z)]]7-[3-[7-[[(2-amino-4-thiazolyl)-[carboxy-(3,4-dihydroxy-5-methoxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]oct-2-en-3-yl]-2-propenyl]-thieno-[2,3-b]-pyridinium(R) or (S) or an (R+S) mixture

The (R) and (S) isomers were separated by HPLC (Microbondapack columnC18), solvent: Water/acetonitril (85/15)

(S) Isomer

NMR analysis of the proton (DMSO 300 MHz in ppm): 3.71 (s): Ar--OCH₃5.16 (d J=5): CO--NH--CH(C═O)--CH--(N--)--S-- 5.32 (s):Ar--CH(CO--O--)--O-- 5.68 (d): --CH═CH--CH₂ --N⁺, 5.79 (dd J=5 and 7.5):CO--NH--CH(C═O)--CH(N--)--S-- 6.28 (m): --CH═CH--CH₂ --N⁺, 6.55 (s)(2H): Ar--H in ortho and para position of the --OMe 6.78 (s):--S--CH═C(C═N--)--N═C(NH₂)-- 7.11 (d): --CH═CH--CH₂ --N⁺, 7.29 (m), 8.38(m), 8.99 (m): mobile H's 7.88 (d): H in position 3 of thethieno-[2,3-b]-pyridinium 8.15 (dd): H in position 5 of thethieno-[2,3-b]-pyridinium 8.29 (d): H in position 2 of thethieno-[2,3-b]-pyridinium 9.08 (d): H in position 4 of thethieno-[2,3-b]-pyridinium 9.22 (d): H in position 6 of thethieno-[2,3-b]-pyridinium 9.55 (d): CO--NH--CH (C═O)--CH(N--)--S--

(R) Isomer

NMR analysis of the proton (DMSO 300 MHz in ppm): 3.50 (s) (partlymasked): C═C--CH₂ --S-- 3.72 (s): Ar--OCH₃ 5.19 (d J=5):CO--NH--CH(C═O)--CH--(N--)--S-- 5.32 (s): Ar--CH(CO--O--)--O-- 5.68 (dJ=6): --CH═CH--CH₂ --N⁺ 5.76 (dd J=5 and 7.5):CO--NH--CH(C═O)--CH(N--)--S-- 6.29 (m): --CH--CH--CH₂ N⁺, 6.55 (s) and6.57 (s) (2H): ar--H in ortho and para position of the --OMe 6.74 (s):--S--CH═C(C═N--)--N═C(NH₂)-- 7.15 (d): --CH═CH--CH₂ --N⁺, 7.30 (m) (2H),8.39 (s) (1H), 8.96 (s) (1H): mobile H's 7.89 (d): H in positio 3 of thethieno-[2,3-b]-pyridinium 8.15 (dd): H in position 5 of thethieno-[2,3-b]-pyridinium 8.29 (d): H in position 2 of thethieno-[2,3-b]-pyridinium 9.08 (d): H in position 4 of thethieno-[2,3-b]-pyridinium 9.23 (d): H in position 6 of thethieno-[2,3-b]-pyridinium 9.62 (d): CO--NH--CH(C═O)--CH(N--)--S--

EXAMPLE 12 The internal salt of[[6R-[3(E),(6α,7β(Z)]]1-[3-[7-[[(2-amino-4-thiazolyl)-[carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl]-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0.]-oct-2-en-3-yl]-2-propenyl]-quinolinium(R) or (S) or (R+S) mixture EXAMPLE 13 The internal salt of[[6R-[3(E),6α,7β(Z)]]2-[3-[7-[[(2-amino-4-thiazol)-[carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]isoquinolinium(R) or (S) or an (R+S) mixture

Rf=0.6 (eluant: acetone-water (8-2))

EXAMPLE 14 The internal salt of[[6R-[3(E),6α,7β-(Z)]]1-[3-[7-[[(2-amino-4-thiazolyl)-[carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-propenyl]-4-(methylthio)pyridinium(R) or (S) or an (R+S) mixture

Rf=0.6 (eluant:acetone-water (8-2))

EXAMPLE 15 The internal salt of[(+)(cis(Z)]7-[3-[7-[[(2-amino-4-thiazolyl)-[carboxy-(3-bromo-4,5-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-(E)-propenyl]-thieno-[2,3-b]-pyridinium(R) or (S) or an mixture EXAMPLE 16 Internal salt of(6R(3(E),6α,7β(Z)))1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dihydroxy-4-fluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo-(4,2,0)-oct-2-en-3-yl)-2-propenyl)quinoliniumSTEP A: Diphenylmethyl[4-fluoro-(2,3-bis-hydroxy)-phenyl]-hydroxy-acetate

480 ml of a 0.3M solution of diphenyl diazomethane were added over 2hours to a solution of 47.7 g of the product of Preparation 11 in 500 mlof ethyl ether cooled to -10° C. The temperature was taken to -5° C. and10 ml of acetic acid were added and the solution was used as is in thefollowing steps.

STEP B: Diphenylmethyl[4-fluoro-[2,3-bis-[(2-methoxyethoxy)-methoxy]-phenyl]hydroxy-acetate

238 ml of diisopropylethylamine were added to the solution of Step A andthe ether was replaced by 500 ml of methylene chloride. Then, themixture was cooled to 6° to 10° C. and 53 ml of methoxyethoxymethylchloride were added over 75 minutes. The mixture was stirred for 75minutes and 500 ml of water were added, followed by decanting. Theorganic phase was washed with N hydrochloric acid, then with N sodiumhydroxide and with water, followed by drying and evaporating to dryness.The residue was chromatographed on silica and eluted with an ethylacetate--hexane (1-1) mixture to obtain 26.1 g of crude product whichwas chromatographed again on silica, eluant: methylene chloride--acetone(97-3) to obtain 14.58 g of the desired product.

NMR Spectrum: CDCl₃ 300 MHz in ppm:

3.34-3.36: the C--O--Me's; 3.52-3.80-3.91: the O--CH₂ --CH₂ --O's; 4.06(dJ=6.5); mobile H; 5.17 to 5.27; the O--CH₂ --O's; 5.49 (dJ=7.5): theC₆ H₅ --CH--O's; 6.84 (dd: J=9 and 10): H₆ ; 6.96 (dd J=9 and 6): H₅ ;7.20 to 7.40 and 6.94 (sl): the aromatics.

STEP C: Diphenylmethyl[4-fluoro-2,3-bis-[[2-methoxyethoxy)-methoxy]-phenyl]-phthalimidoxyacetate

Using the procedure of Step C of Example 4, 14.42 g of the product ofStep B were reacted to obtain after chromatography on silica, eluantmethylene chloride--methanol (99-1), 11.89 g of the desired product.

IR Spectrum CHCl₃ 1792-1756-1734 cm⁻¹ : C═O; 1600-1492 cm⁻¹ : aromatic.

NMR Spectrum: CDCl₃ 250 MHz: for 2 OMEM groups: 3.30 (s), 3.34 (s): OCH₃; 3.47 (m) 3.84 (m): O--CH₂ --CH₂ --O; 5.10-5.27; O--CH₂ O; then 6.39(s): AR--CH(ON═)--CO₂ ; 6.95 (s) CO₂ CH(C₆ H₅)₂ ; 6.84 (t): H₅ ; 7.15(2H) 7.19-7.32 (9H) 7.74 (4H): aromatic H's.

STEP D: Diphenylmethyl aminoxy[4-fluoro-2,3-bis-[2-methoxyethoxy)-methoxy]-phenyl]-acetate

0.88 ml of hydrazine hydrate were added over one hour at -10° C. to asolution of 11.27 g of the product of Step C, 112.7 ml oftetrahydrofuran and the mixture was stirred for 90 minutes at Theinsoluble part was filtered off and the filtrate was concentrated todryness. The residue was chromatographed on silica (eluant: methylenechloride--ethyl acette (80-20)) to obtain 4.72 g of the desired product.

NMR Spectrum: CDCl₃ 200 MHz: 3.35 (s) 3.36 (s): OCH₃ ; 3.54 (m) (4 H)3.93 (m) (4H): O--CH₂ --CH₂ O; 5.20 (s) 5.27 (s): OCH₂ O; 6.78 (dd J=9.5and 9): H₅ ; 6.89 (m): H₆ ; 5.73 (s): Ar--CH(ONH₂)--CO₂ ; 6.94 (s): CO₂--CH--(C₆ H₅)₂ ; 7.10 (m) (5H): 10 aromatic H's (C₆ H₅)₂.

STEP E:[[[1-[4-fluoro-2,3-bis-[(2-methoxy-ethoxy)-methoxy]phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]oxy]-imino]-[2-[(triphenylmethyl)-amino)-amino]-thiazol-4-yl]-aceticacid

Using the procedure of Step E of Example 1, 4.65 g of the product ofStep D and 3.45 g ofoxo-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetic acid (BelgiumPatent Application No. 864,828) were reacted to obtain afterchromatography on silica (eluant: methylene chloride--methanol (96-4))6.5 g of the desired product.

IR Spectrum (CHCl₃): 3410 cm⁻¹ ; ═CH--NH--; 1781 cm⁻¹ : C═O; 1618, 1607,1528, 1496 cm⁻¹ : CO₂, aromatic and heteroaromatic.

NMR Spectrum: DMSO 300 MHz: 3.18 (s) -3.20 (s): OCH₃ ; 3.43 (m) (4H)3.81 (m) O--CH₂ --CH₂ --O--; 5.17 (s) (2H) 5.21 (s) (2H): O--CH₂ --O;5.87 (s) ArCH(O--NH₂) --CH₂ --; 6.68 (s) (3/4H) : H₅ thiazole; 6.84 (s)(3/4H): CO₂ CH(C₆ H₅)₂ ; approx. 6.95-7.0: H₅ H₆ ; approx. 7.18-7.50:other aromatics; 8.65 (sl): ═C--NH.

STEP F: 4-methoxy-benzyl7β-[[[[[1-[4-fluoro-2,3-bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]oxy]-imino-[2-(triphenyl-methyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylate

Using the procedure of Step F of Example 1 but at a temperature of -10°C., 6.44 g of the product of Step E were reacted to obtain afterchromatography on silica [eluant: methylene chloride--ethyl acetate(90-10)], 5.35 g of the desired product were obtained.

NMR Spectrum: (CDCl₃ 400 MHz); 3.05 (d, 1H)--3.20 (d,1H): CH₂ S; [3.24(s), 3.26 (s)](3H) 3.35 (s, 3H): OCH₃ ; 3.43 (m, 2H)--3.55 (m,2H)--3.70-4.15: (CH₂ CH₂ O and ═CH--CH₂ Cl; 3.51 (s): CH₃ OAr; 4.96 (d)-4.97 (d) : H₆ cephalo; 5.12 5.31 (6-7H): OCH₂ O, Cl₂ CH₂ Ar,ArCH(ONH₂)--CO₂ --; 5.81 (m): H₇ cephalo; 5.75 (m): CH═CH--CH₂ Cl (Z);6.26 (d, J═11)--6.29 (d, J═11): --CH═CH--CH₂ Cl (Z) ; approx. 6.77: H₅thiazole; approx. 6.85-7.45: aromtic H's+CO₂ CH(c₆ h₅)₂ ; 7.85-8.20: NH.

STEP G: 4-methoxhy-benzyl 7β-[[[[[1-[4-fluoro-2,3-bis[(2-methoxy-ethoxy)-methoxy]-[phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]oxy]-imino]-2-(triphenyl-methyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-iodo-1-propenyl]-8-oxo-5-thia-l-azabicyclo-[4,2,0[-oct-2-en-2-carboxylate

Using the procedure of Step G of Example 1, 1.2 g of the product of StepF wree reacted to obtain 1.05 g of the desired product.

NMR Spectrum: 3.23 (s) 3.26 (s) 3.35 (s): CH₃ O; aporox. 3.50 to 3.95:O--CH₂ --CH₂ --O of which 3.81: CH₃ OAr; approx. 4.0: ═CH--CH₂ --I; 4.92(m) : H₆ cephalo; 5.16-5.30: OCH₂ O, CO₂ CH₂ Ar; 5.50 (m): H₇ cephalo;6.12 (m): ═CH--CH₂ I (E); 6.42 (s) 6.44 (s): Ar-CH(ONH₂)CO₂ ; 6.66 (t,J═9, approx. ═0.5H): aromatic H in ortho position of F; 6.76 (sresolved): H₅ thiazole; 6.77-7.45: aromatic H's; 7.95 (d) 8.25 (d): NH.

STEP H:1-[3-[7β-[[[[1-[4-fluoro-3,3-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-2-triphenylmethyl)-amino]-thiazol-4-yl]acetamido]-2-[(4-methoxy-benzyloxy)carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-[oct-2-en-3-yl]-2-propenylquinolinium iodide

Using the procedure of tep H of Example 1, 1.02 g of the product of StepG and 0.46 g of quinoline were reacted to obtain after chromatography onsilica, eluant: methylene chloride--methanol (97-3), 347 mg of thedesired product (50/50 mixture of the two R and S isomers of expectedproduct).

NMR Spectrum: (CDCl₃ 400 MHz): 3.20 (s) 3.26 (s) 3.34 (s) 3.35 (s): CH₃O; 3.79 (s) 3.80 (s): CH₃ OAr; 3.42 (m) 3.54 (m) 3.79 (m) 3.90 (m): OCH₂CH₂ O; 4.89 (d) : H₆ cephalo; 5.12 to 5.28:OCH₂ O, CO₂ CH₂ Ar; 5.77 (dd)resolved) H₇ cephalo; 6.00 (dd) 6.13 (dd): ═CH--CH₂ --N═; 6.38 (s) 6.44(s): Ar--CH--(O--) CO₂ ; 6.51 (m): ═CHCH₂ (E); 6.72 (resolved) H₅thiazole; 6.70 to 7.15 H₅ -H₆ fluorophenyl, CH═CH--CH₂, CO₂ CH(C₆ H₅)₂ ;approx. 7.30: aromatic H's (C₆ H₅)₃ --C.

STEP I: Internal salt of (6R(3 (El., 6α,7β(Z)))1-(3-(7-(((2amino-4-thiazolyl)-(carboxy-(2,3-dihydroxy-4-fluorophenyl)methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0 ]-oct-2-en-3-yl)-2-propenyl)-quinolinium

Using the procedure of Step I of Example 1, 339 mg of the product ofStep H and 5 ml of a solution of trifluoroacetic acid with 10%, anisoleto obtain 180 mg of the desired product.

NMR Spectrum: DMSO 300 MHz: 5.15 (d resolved) H₆ cephalo; 5.75 (dd)approx. 5.811-5.95: H₇ cephalo, ═CH--CH₂ N═, Ar--CH(--O--)CO₂ ; 6.38(m): CH═CH--CH₂ (E); 6.99 (d resolved J=16): CH═CH--CH₂ (E); 6.59 (dresolved J=10): H₅ fluorophenyl; 6.75-6.81: H₆ and H₅ thiazole; 7.35(wide): NH₂ and/or C₆ H₅ ; 8.07 (t, 1H) 8.26 (m, 2H), 8.52 (d, 1H) 8.56(dd, 1H) 9.30 (d, 1H) 9.5S (sl 1H): quinoline; approx. =10.50: OH; 9.46(d): CONH.

EXAMPLE 17 Internal salt of (6R(3 (E), 6α,7β-(Z)))7-(3-(7-(((2-amino-4thiazolyl)-(carboxy-(2,3-dihydroxy-4-fluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo(4,2,0) oct-2-en-3-yl)-2-propenyl)-thieno-(2,3,-b) pyridinium

STEP A:1-[3-[7β-[[[[[1-[4-fluoro-2,3-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-[oct-2-en-3-yl-2-propenyl-thieno-(2,3-b)pyridinium iodide

Using the procedure of Step H of Example 16, 944 mg of the product ofStep G of Example 16 and 0.45 g of thieno-[2,3-b]pyridine were reactedto obtain 339 mg of the desired product after chromatographing on silica(eluant: methylene chloride--methanol (95-5)).

NMR Spectrum: CDCl₃ 300 MHz: 3.20 () 3.27 (s) 3.34 (s) 3.35 (s): OCH₃ ;3.40-3.60 and 3.77-4.00: OCH₂ CH₂ O, CH₂ S; 3.79 (s) 3.80 (s): ArOCH₃ ;4.92 (d, J=5) 4.99 (d, J=5): H.sub. 6 cephalo; approx. 5.18-5.30: OCH₂O, CO₂ CH₂ Ar; approx. 5.77 (m): H₇ cephalo; 5.68 (m) 5.96 (m): ═CH--CH₂N═; 6.39 (s) 6.45 (s): ArCH(--O--CO₂ ; 6.73 (s) 6.74 (s): H₅ thiazole;approx. 6.77 (t, resolved): H₅ fluorophenyl; 6.90 to 7.40: benzene H's,CO₂ CH(C₆ H₅)₂, CH═CH--CH₂ (E); 6.92 (m): CH═CH--CH₂ (E); 7.54 (d) 7.66(d) : H₃ ' and 7.83-7.87: H_(2'), and 8.06 (m): H₅ ' and 8.80 (d): H₄ 'and 10.05 (m): H₆ ' and 8.23 (d): CONH of the thieno [2,3-b]pyridine.

STEP B: Internal salt of (6R(3(E),6α,7β(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dihydroxy-4-fluorophenyl]-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl)-2-propenyl)-thieno(2,3,-b) pyridinium

Using the procedure of Step I of Example 16, 332 mg of the product ofStep A were reacted to obtain 164 mg of the desired product.

NMR Spectrum DMSO 300 MHz: 5.18 (d) resolved: H₆ cephalo; 5.67 (d)═CH--CH₂ --N ═; 5.77-5.90: H₇ cephalo, Ar--CH(--O--)CO₂ ; 6.31 (m):CH═CH--CH₂ (E); 7.14 (d, J=15): CH═CH--CH₂ (E); approx. 6.80 (m) : H₅thiazole, H₅ fluorophenyl; 7.36 (wide): NH₂ : 6.59 (t, J=9): H₆ ; 7.899d, J=6) 8.15 (dd) 8.28 (d, J=6) 9.09 (d) 9.23 (d): H₃ 'H₅ 'H₂ 'H₄ 'H₆ 'of the thieno [2,3-b]pyridine.

EXAMPLE 18 Internal salt of (6R(3(E), 6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dihydroxy-4-fluorophenyl]-methoxy)-imino)acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo(4,2,0) oct-2-en-3-yl)-2-propenyl)-4-(methylthio) pyridinium

STEP A:1-[3-[7β-[[[[[1-[4-fluoro-2,3-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3yl]-2-propenyl-4-(methylthio)pyridinium iodide

Using the procedure of Step H of Example 16, 1.052 g of the product ofStep G of Example 16 and 462 mg of 4-thiomethyl pyridine wre reacted toobtain 536 mg of the desired product after chromatography on silica(eluant: methylene chloride--methanol (95-5)).

NMR Spectrum: CDCl₃ 400 MHz: 2.61 (s): CH₃ S; 3.21 (s) 3.26 (s) 3.34 (s)3.35 (s): OCH₃ ; 3.79 (s) 3.88 (s): CH₃ OAr; 3.43 (m) 3.54 (m)3.80-4.00: CH₂ S, OCH₂ CH₂ O; 4.92 (d): H₆ cephalo; 5.70 (dd) +5.77 (dd)H₇ cephalo; 533 (m) 5.54 (m): CH₂ N =; 5.17 5.30: 0CH₂ O, CO₂ CH₂ Ar;6.33 (m): CH═CH--CH₂ (E); 6.35 (s): ArCH(--O--)CO₂ --; 6.74 (s) 6.75(w): H₅ thiazole; 6.72 to 7.18: H₅, H₆ fluorophenyl, CO₂ CHC₆ H₅, rHaromatic, CH═CH--CH₂ (E) ; 7.20 to 7.38: aromatic H C--(C₆ H₅)₃, (C₆H₅)₂ --CH₂ --CO₂ ; 7.61 (d, 2H) 8.8 (m, 2H): H₃ ', H₅ ' and H₂ ', H₆ 'of the pyridinium; 7.83 (d) , 8.15 (d): --CONH.

STEP B: Internal salt of (6R(3(E),6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(crboxy-(2,3-dihydroxy-4-fluorophenyl]-methoxy)imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo(4,2,0) oct-2-en-3-yl)-2-propenyl]-4-(methylthio) pyridinium

Using the procedure of Step I of Example 16, 500 mg of the product ofStep A were reacted to obtain 251 mg of desired product.

NMR Spectrum DMO 300 MHz: 3.50-3.70: CH₂ S; 2.72 (s): CH₃ S; 5.18 (m):H₆ cephalo; approx. =5.77 (m): H₇ cephalo; 5.24 (m): ═CH--CH₂ --N=; 5.83(s), 5.87 (s): OCH₂ O, ArCO₂ CH₂ ; 6.28 (m): CH═CH--CH₂ (E); 6.98 (d,J=16): CH═CH--CH₂ ; 6.61 (t, resolved): H₆ fluorophenyl; 6.77 6.82: H₅and H₆ thiazole; 7.32: NH₂ ; 7.96 (d) 8.71 (d): H₃ ' H₅ ' and H₂ ' H₆ 'of the pyridinium.

EXAMPLE 19 Internal salt of (6r(3(E), 6α,7β(Z)))-2-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dihydroxy-4-fluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo(4,2,0) oct-2-en-3-yl)-2-propenyl) isoquinolinium

STEP A:1-[3-[7β-[[[[[-1-[4-fluoro-2,3-bis-[[2-methoxy-ethoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxybenzoyloxy-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-[oct-2-en-3-yl]-2-propenylisoquinolinium iodide

Using the procedure of Step H of Example 16, 917 mg of the product ofStep G of example 16 and 416 mg of isoquinoline were reacted to obtain473 mg of desired product after chromatography on silica (eluant:methylene chloride--methanol (96.4)).

NMR Spectrum: CDCl₃ 300 MHz: 3.20 (s) 3.26 (s) 3.34 (s) 3.35 (s): CH₃ O;3.76 (s) 3.78 (s): ArOCH₃ ; 3.40-4.00:OCH₂ --CH₂ O, CH₂ S; H₆ cephalo;5.80 (m): H₇ cephalo; approx. 5185.30: OCH₂ O, ArCO₂ CH₂ ; approx. 6.48(m): CH₂ --CH(E); 6.38 (s) 6.44 (): Ar--CH(--O--)CO₂ --; 6.73 (s) 6.75(s): H₅ thiazole; approx. =6.76 to 7.49: aromatic H's (phenyl groups),CO₂ CH(C₆ H₅)₂ ; 7.96 (m, 1H) 8.10 (m, 2H) 8.26 (m, 2H) 8.49 (m, 1H)8.69 (m, 1H) 10.90 (s resolved, 1 h): of the isoquinoline.

STEP B: Internal salt of (6R(3(E), 6α,7β(Z)))2-(3-(7(((2-amino-4-thiazolyl)-(carboxy-(2,3-dihydroxy-4-fluorophenyl)-methoxy]-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo(4,2,0) oct-2-en-3-yl]-2-propenyl) isoquinolinium

Using the procedure of Step I of Example 16, 460 mg of the product ofStep A were reacted to obtain 176 mg of the expected product.

NMR Spectrum: DMSO 400 MHz: 3.72 (m): CH₂ S; 5.18 (d, resolved): H₆cephalo; 5.77 (dd,d after exchange)--H₇ cephalo; 5.52 (m): CH₂ --N═;5.83 (s), 5.87 (s): Ar-CH₂ (--O--) CO₂ ; 6.39 (m): CH═CH--CH₂ (ΔE); 7.10(d, J=10 ): CHCH--CH₂ (E); 6.59 (m), 6.80 (m): H₆, H₅ fluorophenyl; 6.77(s) 6.80 (s): H₅ thiazole; 8.09 (t) 8.28 (t) and 8.37 (d) 8.53 (d) 8.61(d) 8.74 (m) 10.06 (s): H₆ '-H₇ ' and H₃ ' H₄ ' and H₅ ' and H₈ ' and H₁' of the isoquinoline.

EXAMPLE 20 Internal salt of (6R(E(E) 6α,7β(Z)))1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dihydroxy-4-fluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0)oct-2-en-3-yl)-2-propenyl)-imidazo(1,2-a) pyridinium

STEP A:1-[3-[7β-[[[[[1-[4-fluoro-2,3-bis-[(2-methoxy-ethoxy]methoxy]-phenyl]-2-oxo-2-diphenyl-methoxy)-ethyl]-oxy]-imino[2-(triphenylmethy)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0][oct-2-en-3-yl]-2-propenyl-imidazo-(1,2-a) pyridinium iodide

Using the procedure of Step H of Example 16, 955 mg of the product ofStep G of Example 16 and 401 mg of imidazo [1,2-a]pyridine were reactedto obtain 486 mg of expected product after chromatography on silica,eluant: methylene chloride--methanol (95:5).

NMR Spectrum: CDCl₃ 399 MHz 3.20 (w) 326 (s) 3.34 (s) 3.35 (s): CH₃ O;3.40-3.95: OCH₂ --CH₂ O, CH₂ S; 4.89 (d): H₆ cephalo; 5.74 (m): H₇cephalo; 5.20-5.42 (9H, excess): ArCO₂ CH₂ --OCH₂ O, CH--CH₂ N =; 6.28(m): ═CH-CH₂ (E); 6.38 (s) 6.44 (s): Ar--CH(--O--)CO₂ ; 6.88 (s) 6.90(s): CO₂ CH(C₆ H₅)₂ ; approx. 6.75 to 7.35: aromatic H's (phenylgroups)+nitrogenous bicyclic H's; 7.85 (m, 1H) 8.03 (d, 1H) 8.36 (d, 1H)9.09 (m, 1H); other nitrogenous bicycle H's; 7.94 (d), 8.25 (d): CONH.

STEP B: Internal salt of (6R(3(E), 6α,7β(Z)))1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dihydroxy-4-fluorophenyl)methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo(4,2,0)oct-2-en-3-yl)-2-propenyl)imidazo (1,2-a) pyridinium

Using the procedure of Step I of Example 16, 476 mg of the product ofStep A were reacted to obtain 215 mg of desired product.

NMR Spectrum: (DMSO, 400 MHz 3.70 (m): CH₂ S; 5.15 (d, resolved): H₆cephalo; 5.74 (dd, d after exchange) 5.82 (dd, d after exchange): H₇cephalo; 5.28 (m): CH₂ --N; 5.83 (s), 5.86 (s): Ar--CH(--O--)CO₂ ; 6.25(m): CH═CH--CH₂ (E); 6.89 (d, resolved, J=15.5): CH═CH--CH₂ (E); 6.60(m), 6.78 (m): H₆, H₅ fluorophenyl; 6.76 (s) 6.80 (s): H₅ thiazole; 7.57(m) 8.05 (m) 8.19 (m) and 8.28 (d, resolved. J=2.5) 8.44 (d, resolved,J=2.5) 8.96 (d, J=6.5): H₅ 1', H₆ ', H₇ ', H₄ ' and H₂ ', H₃ ' of theimidazo (1,2-a)pyridinium; 9.44 (d) 9,56 (d) CONH-C; 7.32 (m) 9.40 (m):mobile H's.

EXAMPLE 21 Internal salt of (6R-(3-(E)6α,7β(Z))-1(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dihydroxy-phenyl)-methoxy-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-4-(methylthio)pyridinium

STEP A: Ethyl [(2,3-dihydroxy)-phenyl]-hydroxy acetate

10 ml of a molar solution of titanium chloride in methylene chloridewere added to a solution of 1.1 g of pyrocatechol in 20 ml of methylenechloride cooled to -20° C. and the mixture was stirred for 30 minutes at-20° C. Then, a solution of 1.02 g of ethyl glyoxylate in 10 ml ofmethylene chloride was added over 5 minutes and the mixture was stirredfor 2 hours at -20° C. The mixture was allowed to return to ambienttemperature and then was poured into 50 ml of a saturated solution ofammonium chloride, extracted with methylene chloride. The extracts werewashed, dried and evaporated to dryness under reduced pressure. Theresidue was chromatographed on silica (eluant: methylene chloride--ethylacetate (7-3)), to obtain 860 mg of the desired product melting at 86°C.

IR Spectrum: CHCl₃ 3595 cm⁻¹, 340 c,⁻¹ OH complex+associated, 1730 cm⁻C═O, 1602-1402 cm⁻¹ : aromatic.

NMR Spetrum: CDCl₃ 250 MHz ppm 5.33 (s): C--CH(OH)COOEt; 1.26 (t)--4.27(m): COOEt; 3.75-5.86-7.45: mobile H; 6.7 to 6.95: aromatic H's.

STEP B: Ethyl [2,3-bis-[(2-methoxy ethoxy)-methoxy]-phenyl]hydroxyacetate

15.69 g of methoxy ethoxy methyl chloride and 16.35 g of N-ethyldiisopropylamine were added to a solution of 8.1 g of the product of StpA in 750 ml of acetonitrile and the mixture was stirre for 16 hours at0° C. Then, the mixture was poured into 100 ml of water and theacetonitrile was evaporated off, followed by taking up in methylenechloride, washing with 1N hydrochloric acid, with water, then with a 10%solution of sodium carbonate. After drying and evaporating to drynessunder reduced pressure, the 12.3 g of product was chromatographed onsilica (eluant: cyclohexane --ethyl acetate (5-5)) to obtain 6.7 g ofthe desired product.

IR Spectrum: CHCl₃ 3315-3440 cm⁻¹ : OH complex; 1735 cm⁻¹ : C═O;1601-1590 cm⁻¹ : aromatics.

NMR Spectrum: CDCl₃ 250 MHz 1.21 and 4.22: CO₂ Et; 3.37: OCH₃ ;3.57-3.83-3.93: CH₂ --CH₂ --O; 5.25-5.28: O--CH₂ --O; 4.07: OH; 5.39:C--CH(OH)--CO₂ Et.

STEP C: Diphenylmethyl[2,3-bis-[[2-methoxy-ethoxy)-methoxy]phenyl]-hydroxy acetate

a) Saponification:

22 ml of 2N sodium hydroxide were added to a solution of 8.54 g of theproduct of Step B in 400 ml of ethanol and the mixture was stirred for 3hours at ambient temperature, followed by acidifying to pH 2 with a Nhydrochloric acid, concentrating to 1/2 volume under reduced pressure,diluting with 200 ml of water and extracting with methylene chloride andethyl acetate. The extracts were dried and after evaporating to drynessunder reduced pressure, 8.2 g of[2,3-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-hydroxy acetic acid wereobtained.

b) Esterification

109 ml of diphenyl diazomethane in a 0.3M solution in ethyl ether wereadded to a solution of 8.2 g of the above acid in 300 ml of methylenechloride cooled to 0° C. and the mixture was stirred for 16 hours atambient temperature. Acetic acid was added at 0° C. followed byevaporation to dryness under reduced pressure to obtain 13 g of productwhich was chromatographed on silica, eluant: cyclohexane --ethyl acetate(6-4) to obtain 10.2 g of the desired product.

IR Spectrum: CHCl₃ 3530-3520 cm⁻¹ : OH complex; 1742 cm⁻¹ : C═O;1600-1585-1495 cm⁻¹ : aromatics.

NMR Spectrum CDCl₃ 300 MHz 3.34-3.37: CH₃ ; 3.54-3.83: O--CH₂ --CH₂ ;4.08:, 5.18-5.28: OCH₂ O; 5.53: C--CH(OH)C--(C₆ H₅)₂.

STEP D: Diphenylmethyl[2,3-bis-[(2-methoxy-ethoxy)-methoxy]phenyl]-phthalimidoxy acetate

226 mg of triphenyl phosphine and 77 mg of N-hydroxy phthalimide wereadded at ambient temperature to a solution of 227 mg of the product ofStep C in 25 ml of tetrahydrofuran. The mixture is cooled to -5° C. and136 ul (150 mg) of diethylazodicarboxylate were added over 2 hours. Themixture was stirred for 2 hours while allowing the temperature to riseto ambient and was then pourd into 25 ml of ice-cooled water, extractedwith methylene chloride then with ethyl acetate. The extracts were driedand evaporated to dryness under reduced pressure to obtain 760 mg ofresidue which was chromatographed on silica (eluant: methylenechloride--acetone (97-3)) to obtain 230 mg of the desired product.

IR Spectrum: CHCl₃ 1794-1738 cm⁻¹ : C═O; 1602-1588-1488 cm⁻¹ :aromatics.

NMR Spectrum: CDCl₃ 300 MHz 3.31 3.36: CH₃ ; 3.46-3.52-3.79-3.89: CH₂--CH₂ --O; 5.24: O--CH₂ --O; 6.43: C--CH(ON═)CO₂ C--(C₆ H₅)₂ ; 6.95:CH--(C₆ H₅)₂ ; 7.72: Ar-H phthalimido; 7.0-7.35: Ar-H aromatic.

STEP E: Diphenylmethyl aminoxy[2,3-bis-[(2-methoxy-ethoxy)methoxy]-phenyl]acetate

1.42 ml of (1.47 g) of hydrazine hydrate were added to a solution of 6.2g of the product of Step D in 400 ml of ethanol and 20 ml of methylenechloride and the mixture was stirred for 3 hours at ambient temperature.After evaporating to dryness under reduced pressure, the dry extract wastaken up in methylene chloride and the insoluble part was filtered out.The filtrate was evaporated to dryness under reduced pressure to obtain5.0 g of desired product.

IR Spectrum CHCl_(3:) 3335 cm⁻¹ : ONH₂ ; 1745 cm⁻¹ : C═O; aromatics1602, 1589, 1577, 1495 cm⁻¹ aromatics.

NMR Spectrum: CDCl₃ 250 MHz 3.35-3.37: OCH₃ ; 3.54-3.83-3.95: O--CH₂ CH₂--O; 5.26-5.29: O--CH₂ --O--; 5.75: --C--CH(ONH₂)CO₂ C--(C₆ H₅)₂ ; 5.86:O--NH₂ ; 6.95: COO--CH (C₆ H₅)₂.

STEP F:[[[1-[2,3-bis-[(methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)ethyl]-oxy]-imino]-[2-triphenyl-methyl)-amino]-thiazol-4-yl]aceticacid

A mixture of 5.0 g of the product of Step E in solution in 60 ml ofmethanol with 4.016 g of[2-[(triphenyl-methyl)-amino]-thiazol-4-yl]acetic acid described inBelgian Patent Application No. 864,828) was stirred for 6 hours. Afterevaporating to dryness, the residue was chromatographed on silica,eluant: ethyl acetate--ethanol (7-3) to obtain 5.55 g of desiredproduct.

IR Spectrum: CHCl₃ ═C--NH: 3405 cm⁻¹ ; C═O :1735 cm⁻¹ ; C═N, aromaticand CO₂ ⁻ : 1619-1602-1529-1494 cm⁻¹

NMR Spectrum: CDCl₃ 250 MHz 3.13-3.31: CH₃ ; 3.34-3.49-3.76: O--CH₂--CH₂ --O; 5.14-5.18 O--CH₂ --O; 6.11: --C--CH(ON═)CO₂ C--; 6.46: --CO₂--CH(C₆ H₅)₂ ; 6.81: CH thiazol; 6.75 to 7.3 aromatic H's.

STEP G: 4-methoxy-benzyl7β-[[[[[1-[2,3-bis-[(2-methoxy-ethoxy]methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-[(triphenyl-methyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylate

3.55 g of 4-methoxy benzyl7β-amino-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylatehydrochloride (described in EP Application No. 0,333,154) and 1.6 g ofN-ethyl dimethylaminopropyl carbodiimide (EDAC) were added to a solutionof 6.18 g of the product of Step F in 150 ml of methylene chloride andcooled to 0° C. The mixture was stirred for 10 minutes at 0° C. then for2 hours while allowing the temperature to rise 20° C. The mixture waspoured into a molar solution of potassium hydrogen phosphate andextraction took place with methylene chloride, then with ethyl acetatefollowed by drying and evaporating to dryness. After chromatography onsilica and eluting with methylene chloride--ethyl acetate (9-1), 5.1 gof the desired product were obtained.

IR Spectrum: CDCl₃ 3040 cm⁻¹ : ═C--NH; 1790-1731-1684 cm⁻¹ : C═O;aromatics heteroatom, amide II: 1613, 1597-1526-1517-1496 cm⁻¹.

NMR Spectrum: CDCl₃ (300 MHz) 3.24 to 3.37: CH₂ --O--CH₃ and C--s--CH₂--; 3.44 to 4.0:CH₂ Cl and C₆ H₅ OCH₃ ; 3.44 to 4.0: O--CH₂ --CH₂ --;5.15 to 5.28: --O--CH₂ --O; 5.67 to 5.88, 6.29: C--CH--CH₂ Cl; 6.77: CHthiazol; 6.7 to 7.4: aromatics; 8.01-8.37: NH.

STEP H: 4-methoxy-benzyl7β-[[[[[1-[2,3-bis[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-2-(triphenyl-methyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-2-carboxylate

0.57 g of sodium iodide and 1 crystal of iodine were added to a solutionof 1.25 g of the product of Step G in 5 ml of acetone and the mixturewas stirred for 90 minutes at ambient temperature. After evaporating todryness under reduced pressure, the dry extract was taken up inmethylene chloride, washed with a 10% solution of sodium thiosulfate,then with salt water, followed by drying and evaporating to drynessunder reduced pressure to obtain 1.28 g of the expected product which isused as is for the following step.

STEP I:1-[3[7β-[[[[[1-[2,3-bis-[(2-methoxy-ethoxy)-methoxy]phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]-[oct-2-en-3-yl]-2-propenyl]-4-methyl-thiopyridinium iodide

1.28 g of the product of Step H, 1.15 g of thiomethyl pyridine and 3 mlof methylene chloride were mixed together and after evaporating todryness under reduced pressure, the residue was chromatographed onsilica (eluant: methylene chloride--methanol (97-3), then (96-4) and(95-5)) to obtain 415 mg of the desired product.

NMR Spectrum: CDCl₃ 250 MHz 2.6: S--CH₃ ; 3.21, 3.25, 3.35, 3.36, 3.37:--OCH₃ ; 3.4 to 3.9: --OCH₂ --CH₂ --O; 3.77, 3.79 C₆ H₅ --OCH₃

STEP J: Internal salt of (6R-(E) 6α,7β-(Z)))1-3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl)-2-propenyl)-4-(methylthio)pyridinium

400 mg of the product of Step I, 4.5 ml of trifluoroacetic acid and 0.5ml of anisole were stirred for 2 hours at ambient temperature and then,0.5 ml of water were added. The mixture was stirred for 2 hours atambient temperature, followed by filtering, rinsing twice with 3 ml oftrifluoroacetic acid and 15 ml of ethyl ether were added. The mixturewas stirred for 15 minutes, followed by separating and drying underreduced pressure to obtain 222 mg of the desired product.

MR Spectrum: DMSO (300 MHz) ppm 2.71 SCH₃ ; 3.72: C--S--CH₂ --C; 5.19,5.76, 5.83; --S--CH--(--N═)--CH--NH--; 5.22: --C═C--CH₂ --N⁺ ; 5.91,5.95: H imino-carboxybenzyl; 6.28: --CH═CH--CH₂ --N⁺ ; 6.98:--CH═CH--CH₂ --N⁺ ; 6.59, 6.79: aromatic H's; 6.79 6.83: H thiazol;9.49: NH.

EXAMPLE 22 Internal salt of (6R-(3-(E) 6α,7β-(Z)))7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl)-2-propenyl)-thieno-[2,3-b]-pyridinium

STEP A:1-[3-[7β-[[[[[-[2,3-bis-[(1-methoxy)-ethoxy)-methoxy]phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-[(triphenylmethyl)-amino]-thiazol[4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]-[oct-2-en-3-yl]pyridiniumiodide

Using the procedure of Step I of Example 21, 1.24 g of the of Step H ofExample 21 and 1.28 of thieno (2,3-b) pyridine were reacted to obtainafter chromatography on silica, eluant: methylene chloride--methanol(97-3 then 96-4 and 95-5), 450 mg of the desired product.

IR Spectrum: CHCl₃ ═C--NH: 3404 cm⁻¹ ; C═O: 1790, 1731, 1684 cm⁻¹ ; C═C.aromatics, heteroatoms, amide II: 1613, 1587, 1526, 1517, 1496 cm⁻¹ ;thieno pyridine: 1599 cm⁻¹.

NMR Spectrum: CDCl₃ 300 MHz 3.21, 3.26, 3.34, 3.37: CH₂ --O--CH₃ ; 3.43,3.55, 3.82: --O--CH₂ --O--CH₂ --CH₂ ; 3.80: C₆ H₅ O--CH₃ ; 5.2 to 5.3:O--CH₂ --O--CH₂ --, CO₂ CH₂ C₆ H₅ --O--; 5.90: --CH--CH₂ --N⁺ ; 6.45 to6.6: C--CH═CH--CH₂ --N⁺ ; 6.51 to 6.56: CO₂ --CH(C₆ H₅)₂ ; 6.73: Hthiazol; 6.85 to 8.78: aromatic H's.

STEP B: Internal salt of [6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)-[carboxy-(2,3-dihydroxy-phenyl)-methoxy)-imino)acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno(2,3-b)pyridinium

Using the procedure of Step J of Example 21, 430 mg of the product ofStep A were reacted to obtain 206 mg of desired product.

IR Spectruma: Nujol C═0:1775 cm⁻¹ (β-lactam) 1670 cm⁻¹ (complex);conjugated system, aromatic, NH₂, amide: 1599, 1580, 1520 cm⁻¹.

NMR Spectrum: CDCl₃ 400 MHz 3.69: --S--CH₂ --C--; 5.18, 5.78, 5 86:--NH--CH--CH--S--; 5.67: ═CH--CH--N⁺ ; 5.91, 5.95: --C--CH(O--N═)CO₂ H;6.31 and 7.15: the H's of the propylene; 6.59 and 6.79: aromatic H's;6.78 and 6.82: H thiazol; 7.89 to 9.22: thieno pyridine; 9.49 and 9.61:amide.

EXAMPLE 23 Internal salt of (6R-(S-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl)-imidazo(1,2-a) pyridinium

STEP A:1-[3-[7β-[[[[[1-[2,3-bis-[(2-methoxy-ethoxy)-methoxy]phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0][oct-2-en-3-yl]-2-propenyl]-imidazo (1,2-a) pyridinium iodide

Using the procedure of Step I of Example 21, 1.24 g of the product ofStep H of Example 21 and 1.28 g of imidazopyridine were reacted toobtain 270 mg of expected product.

NMR Spectrum CDCl₃ 400 MHz 3.25, 3.20, 3,35, 3.37: CH₂ OCH₃ ; 3.30 to3.90: OCH₂ --CH₂ --OCH₃ ; 3.30 to 390: --S--CH₂ --C--; 3.78, 3.79: --C₆H₅ OCH₃ ; 4.88 and 5.72: NH--CH--CH--S; 5.10 to 5.50: C--O--CH₂ --OCH₂--, ═C--CH₂ --N⁺ ; 6.28: C--CH═CH--CH₂ --; 6.51 to 6.56:--C--CH(O--N═)CO₂ CH; 6.7 to 7.4: aromatic H, H thiazol, H propylene;7.93, 8.20: NH.

STEP B: Internal salt of (6R-(3-(E) 6α,7β-(Z)))7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dihydroxyphenyl]-methoxy-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl)-imidazo (1,2-a) pyridinium

Using the procedure of Step J of Example 21, 280 mg of the product ofStep A were reacted to obtain 140 mg of desired product.

IR Spectrum: C═O: 17.75, 1670 cm⁻¹ ; conjugated system, aromatic, amideII: 1598, 1530, 1510 cm⁻¹.

NMR Spectrum: DMSO 300 MHz 3.45 to 4.20: --S--CH₂ --; 5.16, 5.76, 5.82:--NH--CH--CH--S--; 5.29: --CH₂ --N⁺ --; 5.91, 5.94: C--CH(--O--N═)CO₂ H;6.26: 1H propylene; 6.58, 6.70 to 6.95: H thiazol, aromatic, 1Hpropylene; 9.47, 9.58: NH; 7.58, 8.06, 8.20, 8.96, 8.29, 8.44: bicycle.

EXAMPLE 24 Internal salt of (6R-(3-(E) 6α,7β-(Z)))7-(3-(7-(([3-amino-4-thiazolyl)-(carboxy-(2,3-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-2-propenyl)-quinolinium

STEP A:1-[3-[7β-[[[[1-[2,3-bis-[(2-methoxy-ethoxy]-methoxy]phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-[[triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0][oct.2-en-3-yl]-2-propenyl]-quinoliniumiodide

Using the procedure of Step I of Example 21, 1.33 g of the product ofStep H of Example 21 and 1.2 g of quinoline were reacted to obtain 475mg of the desired product after chromatography on silica (eluant:methylene chloride--methanol (97-3 then 95-5)).

NMR Spectrum: 3.42 to 3.95: OCH₂ --CH₂ --OCH₃ ; 3.78, 3.79: --C₆ H₄--OCH₃ ; 5.13 to 5.28: --OCH₂ --O--CH₂ --, ═C--CH--(O--N═); 5.96, 6.11:--CH₂ --N⁺ ; 6.49, 6.55: --CO₂ --CH--(C₆ H₅)₂ ; 6.85, 8.93: aromatics.

STEP B: Internal salt of (6R-(3-(E) 6α,7β(Z)))7-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,3-dihydroxy-phenyl)-methoxy)-imino)acetamido)-2-carbooxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)quinolinium

Using the procedure of Step J of Example 21, 465 mg of the product ofStep A were reacted to obtain 255 mg of the desired product.

NMR Spectrum: DMSO 300 MHz 3.3 to 3.8: --S--CH₂ --; 5.15 and 5.78:--NH--CH--CH--S--; 5.91: --C--CH(O--N═)CO₂ H and CH₂ --N⁺ --; 6.39:═C--CH═CH--; 6.99: ═C--CH--CH-- 6.7 to 6.9: aromatic H's; 8.08 to 9.58:bicyclic H.

EXAMPLE 25 Internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-N, N-dimethyl benzenaminium

STEP A: [[[1-[2,5-dichloro-3,4-bis-[(2-methoxy ethoxy)-methoxy]phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]aceticacid

Using the procedure of Step E of Example 1, 3.5 g diphenyl methylaminoxy[2,5-dichloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]phenyl]-acetate inStep E of Example 9) and 2.37 g oxo[2-[(triphenyl-methyl)-amino]-thiazol-4-yl]-acetic acid in BelgianPatent Application No. 864,828 were reacted to obtain afterchromatography on silica (eluant: ethyl acetate--ethanol (9-1)) 5.14 gof the desired product.

NMR Spectrum: 300 MHz CDCl₃ 3.30 (s): OCH₃ ; 3.51, 3.92 (m): --O--CH₂--OCH₃ ; 5.16 (s) 5.15 (s): --O--CH₂ --O; 6.25:CH--CO--CH₂, H₆ ; 7.20 to7.30: aromatic H's.

STEP B: 4-methoxy-benzyl7β-[[[[1-[2,5-dichloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxyl]-imino]-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate

Using the procedure of Step F of Example 1, 4.8 g of the product of StepA and 2.26 g of 4-methoxy-benzyl 7β-amino-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylatehydrochloride (EP Patent No. 0,333,154) were reacted to obtain afterchromatography on silica (eluant: methylene chloride--ethyl ether(9-1)), 4.6 g of desired product.

NMR Spectrum: 300 MHz CDCl₃ 3.05 (m) 3.45 (m): --CH₂ --Cl; 3.36, 3.37(s): --O--CH₃ ; 3.57 (m) 3.97 (m): O--CH₂ --O--; 3.81 (s,d): --o--OCH₃ ;4.99, 5.02 (d): NH--CH--CH--S; 5.86, 5.90: NH--CHCH--S; 5.15 to 5.26:O--CH₂ --O--; 5.75 (m): H₂ propylene; 6.26 (J=11.5) (d) 6.35 (J=11.5)(d): H₁ propylene; 6.47 to 6.50 (s)--CO₂ --CH--o₂ ; 6.85 to 7.40 thearomatic H's.

STEP C: 4 -methoxy-benzyl 7β-[[[[1-[2,5-dichloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]oxy]-imino]-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2carboxylate

Using the procedure of Step G of Example 1, 150 mg of the product ofStep B were reacted to obtain 160 mg of the desired product.

STEP D:1-[3-[7β-[[[[[1-[2,5-dichloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy]-ethyl]-oxy]imino]-2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4.2,0]-oct-2-en-3-yl]-2-propenyl]-N,N-dimethylbenzene aminium iodide

Using the procedure of Step H of Example 1, 155 mg of the product ofStep C and 64 mg of N,N-dimethylaniline were reacted to obtain afterchromatography on silica (eluant: methylene chloride methanol (96-4)),55 mg of the desired product.

NMR Spectrum: CDCl₃ 300 MHz 2.95 (s): ##STR48## 3.30 to 3.45: --S--CH₂--; 3.35, 3.36, 3.37 (s): O--CH₃ ; 3.82 (s,d) φ--OCH₅ ; 3.90 to 4.05:--O--CH₂ CH₂ --O--, ═C--CH₂ --N (CH₃)₂ O; 4.94 (d)--4.98 (d):NH--CH--CH--S; 5.87 (m): NH--CH--CH--S; 5.18 to 5.30 (m): O--CH₂ --O andO--CH₂ --o; 6.14 (m) (E) C--CH═CH--CH₂ --; 6.70 to 7.40 (m)C--CH--CH--CH₂ --, H thiazole, aromatic H's; 8.17, 8.25 (d): NH.

STEP E: Internal salt of (6R--(3--(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-N,N-dimethylbenzene aminium

Using the procedure of Step I of Example 1, 50 mg of the product of StepD were reacted to obtain 22 mg of the desired product.

EXAMPLE 26 Internal salt of (6R-(S-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0.]oct-2-en-3-yl)-2-propenyl)-imidazo(1,2-a)pyridinium

STEP A:1-[3-[7α-[[[[[1-[2,5-dichloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]imidazo(1,2-a)pyridiniumiodide

Using the procedure of Step H of Example 1, 1.24 g of the product ofStep C of Example 25 and 0.497 g of imidazo(1,2-a) pyridine were reactedto obtain after chromatography on silica (eluant: methylenechloride--methanol (95-5)), 625 mg of the desired product.

NMR Spectrum: CDCl₃ 400 MHz 3.34, 3.36: --CH₂ --O--CH₃ ; 3.50, 3.87:O--CH₂ --CH₂ --OMe; 3.80 (s) --o--OCH₃ ; 4.94 (d,d): --NH--CH--CH--S--;5.20, 5.24: --O--CH₂ --O--, Co₂ --CH₂ --φ--; 5.86; NH--CH--CH--S; 6.15,6.35: H propylene; 6.47, 6.51: ═N--O--CH--; 6.77: H thiazole; 6.90 to7.40: the aromatic H's; 7.88, 8.04: H of the imidazole; 7.88: --NHCφ₃.

STEP B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo (1,2-a) pyridinium

Using the procedure of Step I of Example 1, the product of Step A werereacted to obtain 327 mg of desired product.

NMR Spectrum: CDCl₃ 300 MHZ 3.50 to 3.75: --S--CH₂ --C═; 5.16:--NH--CH--CH--S--; 5.79 (m): --NH--CH--CH--S--; 6.24 (m):.tbd.C--CH═CH--C--; 6.91 (dd): ═C--CH═CH--C--; 6.83 (dd): H thiazole;7.58, 8.06 (t) and 8.21, 8.96 (d): H pyridine; 8.29, 8.45: H imidazole;9.62: NH; 993: NH₂, CO₂ H.

EXAMPLE 27 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(([2-amino-4-thiazolyl)-(carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl]-methoxy)imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-6,7-dihydro-5H-pyrindinium

STEP A:1-[3-[7β-[[[[[1-[2,5-dichloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-6,7-dihydro-5H-pyrindinimniodide

Using the procedure of Step H of Example 1) 1.13 g of the product ofStep C of Example 25 and 457 mg of cyclopentano [2,3-a] pyridine werereacted to obtain after chromatography on silica (eluant: methylenechloride--methanol (9-1)) 460 mg of the desired product.

NMR Spectrum: CDCl₃ 300 MHz ppm 2.41, 3.23, 3.45: --S--CH₂ and CH₂ ofthe cyclopentane; 3.34 to 3.37: O--CH₃ ; 3.57 to 3.98: --O--CH₂ --CH₂--O--; 3.81: O--O--ch₃ ; 4.97, 5.88: NH--CH--CH--S--; 5.12 to 5.25:--O--CH₂ --O--; 6.22 and 6.45 (ΔE) ═C--CH--CH--CH₂ --; 6.85 t 7.35:.tbd.C--CH═CH--CH₂ --; 6.46, 6.50 (s) ═N--O--CH--CO₂ --; 6.72: Hthiazole; 6.85 to 7.35: aromatic H's 7.97, 8.23 (d): NH; 7.79, 9.20: Hpyridine.

STEP B4 Internal salt of (6R-(3-(E) 6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-6,7-dihydro-5H-pyrindinium

Using the procedure of Step I of Example 1, 447 mg of the product ofStep A were reacted to obtain 194 mg of the desired product.

NMR Spectrum: DMSO 300 MHz 2.23 (m): the central CH₂ 's; 3.19 (t) the═C--CH₂ 's; 5.17 (d): H₆ ; 5.33 (m): ═CH--CH₂ --N+; 5.78 (m) (2H): theH₇ 's and O--CH--φ's; 6.23 (m): CH₂ --CH═E; 6.82 (s) (d): H₅,thiazole's; 6.89 (d)d) the ═C--CH═CH (ΔE)'s; 7.01 (s d) aromatic H; 7.91(t): H₅ '; 8.42 (d): H₄ '; 8.76 (d): H₆ '; 7.85 (1): NH₂ ; 9.56 to 10.0the mobile H's.

EXAMPLE 28 Internal alt of (6R--(3--(E) 6α,7β-(Z)))1-(3-(-(((2-amino-4-thiazolyl)-carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-1-methyl-pyrrolidinium

STEP A:1-[3-[7β-[[[[[1-[2,5-dichloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-1-methyl pyrrolidinium iodide

Using the procedure of Step H of Example 1, 605 mg of the product ofStep C of Example 25 and 174 mg of N-methyl pyrrolidine were reacted toobtain after chromatography on silica (eluant: methylenechloride--methanol (9-1)), 210 mg of the desired product.

NMR Spectrum: 400 mHz in CDCl₃ 3.49 to 3.72 and 3.97: the central CH₂ 'sand N⁺ CH₃ ; 3.20, 3.33, 3.34: the OCH₃ 's 2.6: pyrrolidine; 4.01, 4.28,4.52; N⁺ --CH₂ ; 5.25: CO₂ --CH₂ --φ and O--CH₂ --O; 6.09 and 6.17═C--CH═CH--CH₂ --; 6.85 to 7.42; ═C--CH═CH₂ -- and CO₂ --CH--φ₂.

STEP B: Internal salt of (6R (3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-1-methyl pyrrolidinium

Using the procedure of Step I of Example 1, 200 mg of the product ofStep A were reacted to obtain 93 mg of the desired product.

NMR Spectrum: DMSO 300 MHz ppm 2.09 (sl): CH₂ in position 3',4';apporox. =3.45 (sl) CH₂ in position 2',5'; 2.99 (s): N⁺ CH₃ ; 3.61 (d,d)and 3.80 (d) 3.86 (d): CH₂ --S; 4.10 (d): ═CH--CH₂ --N⁺ ; 5.21 (d): H₆ ;5.84 (m): H₇ ; 5.78 (s) 5.81 (s) ═C--CH--O; 6.16 (m): CH═CH--CH₂ (ΔE);7.03 (d, J=15) CH═CH--CH₂ ; 7.01 (s) 7.06 (s) 6.83 (s) 6.84 (s): H₅ ofthe thiazole and aromatic 1H; 9.60 (d) 9.66 (d) CONH--CH; 9.95 (m) 7.40(m): mobile H's.

EXAMPLE 29 Internal salt of (6R-(3-(E) 6α,7β-(Z)))1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5,-dichloro-3,4-dihydroxy-phenyl]-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno(2,3-c)pyridinium

STEP A:1-[3-[7β-[[[[1-[2,5-dichloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-thieno-(2,3-c)pyridinium iodide

Using the procedure of Step H of Example 1, 1 g of the product, of StepC of Example 25 and 458 mg of thieno-[2,3-c]-pyridine were reacted toobtain after chromatography on silica (eluant: methylenechloride--methanol (9-1)) 520 mg of the desired product.

NMR Spectrum: CDCl₃ 300 MHz 3.56 (s) 3.98 (s): the central CH₂ 's andS--CH₂ ; 3.79 (s) φ--OCH₃ ; 5.20 to 5.30: O--CH₂ --O and CO₂ --CH₂ --;4.95, 5.26 (m): NH--CH--CH--S; 6.33, 6.48 (m) E: C--CH═CH--; 6.80 to7.40: ═C--CH═CH; 5.59 (m) to 5.80 (m): ═CH--CH₂ --N═; 6.80 to 7.40:aromatic H; 6.77 (sd): H thiazole; 11.50 (s1,d) NH, --N═CH--.

STEP B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7,([(2-amino-4-thiazolyl)-(carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno-(2,3-c) pyridinium

Using the procedure of Step I of Example 1, the product of Step A wasreacted to obtain 114 mg of the desired product.

NMR Spectrum: DMSO 300 MHz 5.19 (d): H₆ ; 5.46 (d) N⁺ CH₂ --CH═; 5.79(m): --O--CH--o, H₇ ; 6.35 (m): ═CH--CH₂ (E); 6.81 (s) d: H₅ thiazole;7.00 (s): H of the phenyl; 7.07 (dJ=16): ═C--CH═CH (E); 7.34 (1): NH₂ ;7.94 (dJ=5,5) H₃ ' 8.76 (dJ═5.5): H₂ '; 8.53 (d, J═6.5) 8.73 (d, J═6.5):H₄ ' and H₅ '; 9.91 (s,1): H₆ '; 9.59 (d,d) ═C--NH--CH; 9.88: mobile H.

EXAMPLE 30 Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(4-cyano-2,3-dihydroxy-phenyl]-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno-(2,3-b)-pyridinium

STEP A: [4-cyano-2,3-bis-[(2-methoxy-ethoxyl-methoxy]phenyl]bromoaceticacid

440 microliters of bromoform were added at -5° C. to a mixture of 4.26mg of lithium bromide, 598 mg of potassium hydroxide and 5 ml of waterand then, a solution of 825 mg of a4-cyano-2,3-bis-[(2-methoxy-ethoxy)-methoxy]-benzaldehyde (preparationgiven hereafter) in 5 ml of dioxane was added dropwise. The mixture wasstirred for 72 hours at 0° C. to -5° C. and was poured into a stirredmixture at 0° C. to -5° C. of 15 ml of ethyl acetate and 11 ml ofhydrochloric acid. Extraction was carried out with ethyl acetate and theextracts were washed, dried and evaporated to dryness under reducedpressure. The oil obtained was used as is for the following step.

STEP B: Diphenylmethyl[4-cyano-2,3-bis-[(2-methoxy-ethoxy)methoxy]-phenyl]-bromoacetate

The product of Step A was dissolved in 10 ml of methylene chloride and470 mg of diphenyl diazomethane were added. Evaporation was carried outfollowed by chromatography on silica (eluant: cyclohexane--ethyl acetate(2-1)) to obtain 450 mg of the desired product.

NMR Spectrum: 3.31 (s), 3.37 (s): (OCH₃ 's: 3.43 (m), 3.61 (m), 3.77(m), 4.05 (m) central CH₂ 's: 5.18 (d), 5.25 (d), 5.29 (AB), OCH₂ O's;6.02 (s): ═CH--X.

STEP C: Diphenymethyl4-cyano[2,3-bis]-[(2-methoxy-ethoxy)-methoxyl-phenyl]-phthalimidoxy-acetate

126 mg of N-hydroxyphthalimide and 196 mg of potassium acetate wereadded to a soluton of 820 mg of the product of Step B in 13 ml ofdimethylformamide and the mixture was stirred for 3 hours at ambienttemperature and evaporated to dryness. Chromatography on silica (eluant:cyclohexane--ethyl acetate (1-1)) yielded 640 mg of the desired productwhich was used as is for the following step.

STEP D: Diphenylmethyl4-cyano-[2,3-bis]-[(2-methoxy-ethoxy)-methoxy]-phenyl]-aminoxy-acetate

Using the procedure of Step D of Example 1, 640 mg of the product ofStep C and 50 microliters of hydrazine hydrate were reacted to obtain320 mg of the expected product.

STEP E:[[[1-[4-cyano-2,3-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]2-[(triphenylmethyl)-amino]-thiazole-4-yl-aceticacid

Using the procedure of Step E of Example 1, 320 mg of the product ofStep C and 234 mg of triphenylamino-thiazol-4-yl acetic acid werereacted to obtain 550 mg of the desired product.

NMR Spectrum CDCl₃ ppm 3.32 (s), 3.37 (s): OCH₃ 's; 3.48 (t) 3.60 (t)3.75 (m) 4.03 (m): centrl CH₃ 's; 5.13 (AB), 5.24 (AB), O--CH₂ --O's;6.27 (s): ##STR49## 6.74 (s): H₅ thiazole; 6.29 (s): --CO₂ --CH--Co₂ ;7.09 to 7.32: aromatic H's; 2.60 mobile H: NH

STEP F:4-methoxy-benzyl-7β-[[[[[1-[4-cyano-2,3,-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-amino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo-oct-2-en-2 carboxytate

Using the procedure of Step F of Example 1, 550 mg of the product ofStep E were reacted to obtain after chromatography on silica (eluant:methylene chloride--ethyl acetate (8-2)), 580 mg of the desired product.

STEP G: 4-methoxy-benzyl7β-[[[[[1-[4-cyano-2,3-bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo-oct-2-en-2-carboxylate

Using the procedure of Step G of Example 1, 580 mg of the product ofStep F were reacted to obtain 615 mg of the desired product.

NMR Spectrum: CDCl₃ 3.25 (s), 3.27 (s), 3.37 (s), 3.2 to 3.6 (m): OCH₃'s and CH₂ S's; 3.44 (m), 3.60 (m), 3.80 (m): central CH₂ 's; 4.01 (m):CH₂ H; 4.93 (d): H₆ ; 5.17 to 5.38 (m): O--CH₂ --O's; 5.78 (dd, 5.86(dd): H₆ ; 6.12 (m): CH═CH--CH₂ ; 6.43, 6.46 (s): O--CH--o; 6.75 (s),6.76 (s): H₅ thiazole; 6.83 to 7.45 (m): aromatic H's, HC═, CO₂ --CH--φ₂; 7.82, 8.15 (d): mobile H: CONH.

STEP H:1-[3-[7β-[[[[[1-[4-cyano-2,3-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0][oct-2-en-3-yl]-2-propenyl]-thieno-(2,3-b)pyridinium iodide

Using the procedure of Step H of Example 1, 615 mg of the product ofStep G and 290 microliters of thieno-(2,3-b)-pyridine were reacted toobtain after chromatography on silica (eluant: methylenechloride--methanol (9-1)), 300 mg of the desired product.

NMR Spectrum: CDCl₃ ppm 3.20 (S), 3.26 (S), 3.35 (S), 3.37 (S): the CH₃O's; 3.43 (m), 3.50 (m), 3.78 (m), 4.02 (m): central CH₂ 's; 3.80, 3.81(s): φ--O--CH₃ ; 4.93 (d,d); H₆ ; 5.76, 5.84 (m): H₇ ; 5.71, 5.96 (m):C--CH₂ --N⁺ ; 6.40, 6.45 (s ): ##STR50## 6.91 (m) ═CH--CH₂ (E); 6.73,6.74 (s): H₅ thiazole; 6.94 (m): aromatic H, --O--CH--φ₂, CH═CH-- (ΔE)7.05 to 7.45: the aromatic H's.

STEP I: Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(4-cyano-2,3-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno-(2,3b) pyridinium

Using the procedure of Step I of Example 1, 292 mg of the product ofStep H were reacted to obtain 176 mg of the desired product.

NMR Spectrum: DMSO 5.18 (d,d): H₆ ; 5.82 (m): H₇ ; 5.68 (d): ═C--CH₂--N⁺ ; 5.93 (s, d): O--CH--o; 6.29 (m): CH₂ --CH═CH-- (ΔE); 6.79 (s,d):H₅ thiazole; 6.94 (d,d), 7.03 (d): aromatic H; 7.89 (d) H₃ ', 8.28 H₂ ',8.15 H₅ '9.22 H₄ ': thieno pyridine; 9.54, 9.69: CO--NH--CH; 10.33:mobile H.

PREPARATION EXAMPLE 304-cyano-2,3-bis-[(2-methoxy-ethoxy)-methoxy]-benzaldehyde

STEP A: 1,4-dicyano-2,3-dihydroxyphenyl

46 g of sodium ethylate were added to a mixture of 400 ml oftetrahydrofuran, 50 g of dicyanoethylsulfide and 52 g of diethyloxalateand the mixture was stirred for one hour and concentrated under reducedpressure. The residue was taken up in 600 ml of water and 250 ml ofethyl acetate and washed with ethyl acetate. The aqueous phase wasacidified with concentrated hydrochloric acid and extraction was carriedout with ethyl acetate. The extracts were evaporated to dryness underreduced pressure and the dry extract was taken up in 400 ml ofnitromethane, followed by separation and washing with water to obtain12.46 g of the desired product with a Rf=0.31 in CH₂ Cl₂ --MeOH 85-15.

STEP B: 1,4-dicyano-2,3-dimethoxy phenyl

A mixture of 1 g of the product of Step A, 60 ml of acetone, 3.15 g ofpotassium acetate and 1.5 ml of dimethyl sulfate was stirred for 16hours at reflux, then cooled, filtered and evaporated to dryness underreduced pressure. The residue was chromatographed on silica (eluant:methylene chloride--hexane (9-1)) to obtain 820 mg of the desiredproduct.

IR Spectrum: (CHCl₃)

conjugated CN 2240 cm⁻¹

aromatic 1595-1555 cm⁻¹

STEP C: 4-cyano-2,3-dimethoxy benzaldehyde

900 ml of toluene were added to a solution of 15.70 g of the, product ofStep B and 61 ml of a 1.5M solution of diisobutyl aluminium hydride intoluene were added over 15 minutes at -74° C. The mixture was stirredfor 30 minutes at -70° C. to -74° C. and 20 ml of acetone were addedslowly. The mixture was stirred for 10 minutes and then was poured into700 ml of 1N hydrochloric acid and 200 ml of ethyl acetate. The mixturewas stirred for 30 minutes at ambient temperature, followed by decantingand extracting with ethyl acetate. The extracts were dried andevaporated to dryness to obtain 15.5 g of the desired product. 4.9 g ofa previous product were added to the dry extract and the 20.4 g of crudeproduct was chromatographed on silica three times, eluting withtoluene--ethanol (95-5) to obtain 7.5g of the desired product.

NMR Spectrum: CDCl₃ 4.06, 4.10: the O--CH₃ 's; 7.38 (d) 7.60 (d):aromatic 2H, ortho coupling; 10.42 (s): CHO.

STEP D: 4-cyano-2,3-bis-[(2-methoxy-ethoxy)-methoxy]-benzaldehyde

124 ml of a molar solution of boron tribromide were added at -70° C. toa solution of 5.9 g of the product of Step C in 150 ml of methylenechloride and the mixture was stirred for 72 hours at ambienttemperature, then cooled to -30° C. 30 ml of methanol were added slowlyand the mixture was stirred for 30 minutes followed by evaporation todryness under reduced pressure. The residue was taken up in 200 ml ofethyl acetate, washed with water, dried and evaporated to dryness underreduced pressure to obtain 6.4 g of residue to which was added 190 ml ofmethylene chloride. After cooling to 0° C., 21 ml of diisopropyl ethylamine and 141 ml of methoxy ethoxy methyl chloride were added and themixture was stirred for 3 hours at ambient temperature. The solution waswashed with N hydrochloric acid, N sodium hydroxide and water, dried andevaporated to dryness. The residue was chromatographed on silica(eluant: methylene chloride--ethyl acetate (9-1)) to obtain 4.93 g ofthe desired product.

NMR Spectrum: CDCl₃ 3.35, 3.38 (s): the O--CH₃ 's; 3.53, 3.62, 3.88,4.08 (m): central CH₂ 's; 5.33, 5.39 (s): O--CH₂ --O; 7.45 (dd=J=8 and0.5 Hz): H6; 7.67 (d, J=8 Hz): H₅ ; 10.39 (d,J=0.5 Hz): CHO.

EXAMPLE 31 Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(4-cyano-2,3-dihydroxy-phenyl)-methoxy)-imino)acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-quinolinium

STEP A:1-[3-[7β-[[[[[1-[4-cyano-2,3-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]quinoliniumiodide

Using the procedure of Step H of Example 1, 615 mg of the product ofStep G of Example 30 and 200 microliters of quinoline were reacted toobtain after chromatography on silica (eluant: methylenechloride--methanol (91-9)), 145 mg of the desired product.

STEP B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(4-cyano-2,3-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)quinolinium

Using the procedure of Step I of Example 1, 230 mg of the product ofStep A were reacted to obtain 137 mg of the desired product.

NMR Spectrum: DMSO 3.30 to 3.8 (m): CH₂ --S; 5.15 (d): H₆ ; 5.60 (dd):H7; 5.91, 5.93 (s): ##STR51## 5.90 (m): CH₂ --N⁺ ; 6.37 (m): HC═CH--CH₂; 6.93 (d, J=16) HC═CH--CH₂ ; 6.78, 6.94 (d): H₅ ', H₆ '; 7.01 (s): Hthiazole; 8.08, 8.28 (t): H₆ ", H₇ ", 7; 8.23 (dd) (J=6 and 8 Hz): H₃ ';8.51 (d) 8.55 (dd): H₅ " and H₄ " or H₈ "; 9.34 (d J=8 Hz) H4" or H₈ ";9.55 (d, J=6 Hz): H₂ "; 9.52 (d) 9.68 (d): HC--NH--CO.

EXAMPLE 32 Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(5-cyano-3,4-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno-(2,3-b)-pyridinium(RS isomer),

STEP A:1-[3-[7β-[[[[[1-[5-cyano-3,4-bis-[(2-methoxy-ethoxy)methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0][oct-2-en-3-yl]-2-propenyl)-thieno-(2,3-b)-pyridiniumiodide (RS isomer)

Using the procedure of Step H of Example 2, 1.5 g of the product of StepG of Example 2 and 1.35 g of thieno-[2,3-b]-pyridine were reacted toobtain 1.22 g of the expected product (R/S mixture).

NMR Spectrum: CDCl₃ 300 MHz 3.27 (s), 3.29 (s), 3.35 (s), 3.36 (s): theC═OMe's; 3.80 (s), 3.81 (s): the ═C--OMe's; 3.30 to 4.10: central CH₂ 'sand CH₂ S's; approx. 5.00 to 5.11: the H₆ 's; approx. 5.20 to 5.40: theO--CH₂ --O's; 6.76 (s) and 6.77 (s): H₅ thiazoles; approx. 6.90 to7.50:COOCHo₂ and C₆ H₅ 's; 9.58 (d) resolved: the H₆ "s; 7.52 to 8.90the other quinoline H's; 8.22 and 8.34 (d): the ═C--NH--CH's.

STEP B: Internal salt of (6R-(3-(E)6α,7β(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(5-cyano-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)-2-propenyl)-thieno-(2,3-b)-pyridinium (R/Smixture)

Using the procedure of Step I of Example 1, 1.2 g of the product of StepA were reacted to obtain 730 mg of the desired product.

NMR Spectrum: DMSO 300 MHz 5.17 (d) resolved): H₆ ; 5.40 (s): ##STR52##5.68 (d): CH-N⁺ ; 5.79 (m): H₇ ; 6.87 (m ): ═C--CH═CH--CH₂ (ΔE); 6.77 (s) and 6.79 (s ): H₅ thiazole; 7.12 and 7.17: aromatic and ═C--CH═CH--;7.89 (d): H₃ '; 8.28 (d): H₂ '; 8.15 (dd): H₅ '; 9.09 (d): H₄ '; 9.23(d) resolved H₆ '; 9.68 (d) resolved: NH; 10.38: mobile H; 7.39 (m):NH₂.

EXAMPLE 33 Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(5-cyano-3,4-dihydroxyphenyl)-methoxy)-imino]acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno-(2,3-b) pyridinium (S isomer)

240 mg of the product were chromatographed on a microbondapack column,eluant: water, acetonitrile 82/18 (pH =2.7) to obtain 45 mg of thedesired product.

NMR Spectrum: DMSO 300 MHz 5.15 (d, J=5): H₆ ; 5.40 (s): O--CH--φ; 5.67(d): ═CH--CH₂ --N⁺ ; 5.80 (dd, J=5 and 8): Hz; 6.25 (m): ═CH--CH₂ ; 6.79(s): H₅ thiazole; 7.13 (m): aromatic and ═CH--CH (ΔE); 7.89 (d, J=6):8.28 (d, J=6): H₃ ' and H₂ '; 8.15 (m): H₅ '; 9.09 (d, J=8): H₄ '; 9.22(d, J=6): H₆ '; 9.62 (d, J=8): ═C--NH--CH; 10.34, 10.43: OH; 7.33: theNH₂ 's.

EXAMPLE 34 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(3-chloro-4,5-dihydroxy-phenyl)-methoxy)imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo-(1,2-a)-pyridinium

STEP A:[[[1-[3-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-[(triphenylmethyl)-amino]-thiazol-4-yl]-aceticacid

Using the procedure of Step E of Example 1, 2.56 g of the product ofStep D of Example 4 and 1.84 g ofoxo-[2-[(triphenyl-methyl)-amino]-thiazol-4-yl]-acetic acid (BelgiumPatent Application No. 864,828) were reacted to obtain afterchromatography on silica (eluant: methylene chloride--methanol (97-3)),3.34 g of the desired product with a Rf =0.54 (CH₂ Cl₂ -MeOH (9-1)).

STEP B: 4-methoxy-benzyl7β-[[[[[1-[3-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate

Using the procedure of Step F of Example 1, 1.42 g of 4-methoxy-benzyl7β-amino-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylatehydrochloride (EP 0,333,154) and 3.34 g of the product of Step A toobtain 2.88 g of the desired product with a Rf=0.44 (CH₂ Cl₂ -ACOEt(8-2)).

STEP C: 4-methoxy-benzyl7β-[[[[[1-[3-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamidol-3-[(S)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate

Using the procedure of Step G of Example 1, 1.88 g of the product ofStep B were reacted to obtain 1.75 g of the desired product with aRf=0.52 (CH₂ Cl₂ -ACOEt (8-2)).

STEP D: 1-[3-[7β-[[[[[1-[3-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-(1,2-a)-pyridiniumiodide

Using the procedure of Step H of Example 1, 876 mg of the product ofStep C and 0.308 ml of imidazo-[1,2-a]-pyridine were reacted to obtainafter chromatography on silica (eluant: methylene chloride--methanol(97-3)) 450 mg of the desired product.

NMR Spectrum (CDCl₃ 300 MHz 3.25, 3.29 (s); 3.35, 3.36 (s): the OCH₃ 's;3.43, 3.55, 3.72, 4.01 (m): the central CH₂ 's and CH₂ S's; 3.78 (s,d)φ--O--Me; 4.94 (d,d) and 5.83 (m): H₆ and H₇ (cis); 5.17 to 5.35 and5.43 (d,t): OCH₂ O, CO₂ CH₂ -φ, NCH₂ --CH═; 5.94 (s): O--CH--φ; 6.25 (m:═CH--CH₂ (ΔE); 6.76 (s): H₅ thiazole; 6.89 --CH--φ₂ ; 6.85 to 7.40:φ--C, aromatic, CH═CH--C═(ΔE) 7.85 (d,d): H₅ ', H₆ '; 8.05 (d,d): H₄ ';8.38 (d,d): H₃ '; 8.64 (d,d): H₁ '; 9.11 (d,d): H₇ '; 7.97 to 8.19 (d)the NH's.

STEP E: Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(3-chloro-4,5-dihydroxylphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo-(1,2a)-pyridinium

Using the procedure of Step I of Example 1, 489 mg of the product ofStep D were reacted to obtain 187 mg of the expected product.

NMR Spectrum: DMSO 300 MHz 3.62: CH₂ S; 5.29 (m): N⁺ --CH₂ --CH═; 5.34(s,d): ##STR53## 6.22 (m): ═CH--CH₂ (E); 6.77 (s): H₅ thiazole; 6.85(s); 6.90: --CH--φ₂, aromatic and CH═CH--CH₂ (ΔE); 7.33: NH₂ and φ--C;5.13 and 5.75: H₆ -H₇ ; 7.58 (t): 8.06 (t): H₅ '-H₆ '; 8.28 (m): 8.44(sl): H₃ '-H₂ '; 8.96 (d): H₄ '; 9.59 (d,d): H₇ '; 9.29 (sl), 13.03,13.66: mobile H.

EXAMPLE 35 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(3-chloro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-4-methylthiopyridinium

STEP A:1-[3-[7β-[[[[[1-[3-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-4-methylthiopyridinium iodide

Using the procedure of Step H of Example 1, 875 mg of the product ofStep C of Example 34 and 385 mg of 4-S-methyl thiopyridine were reactedto obtain after chromatography on silica (eluant: methylene chloridemethanol (97-3 then 90-10)), 389 mg of the desired product.

NMR Spectrum: CDCl₃ 300 MHz 2.61, 2.63: S--CH₃ ; 3.25, 3.28, 3.36, 3.37:the OCH₃ 's; 3.78 (s): 3.79 (s): the oOMe's; 3.44, 3.58, 3.72, 4.01: thecentral CH₂ 's and CH₂ --S's; 4.97 (d,d): H₆ ; 5.05 to 5.35: OCH₂ O, CO₂CH₂ --φ, CH₂ N⁺ (1H); 5.56 (m); 5.85: CH₂ N⁺ (1H); 6.24, 6.39 (m):CH═CHCH₂ (ΔE); 6.78 (sl): H₅ thiazole; 6.89 (sl): CO₂ CH₂ --φ; 7 to7.40: oC, aromatic and ═C--CH═CH--(ΔE); 7.66 (d,d) and 8.90 (m)thiopyridinium.

STEP B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(3-chloro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-4-methylthio pyridinium

Using the procedure of Step I of Example 1, 389 mg of the product ofStep A were reacted to obtain 174.7 mg of the desired product.

NMR Spectrum: DMSO 300 MHz 2.72: SCH₃ ; 3.49 (s); 3.549 (d); 3.71 (d):CH₂ S; 5.13, 5.17 (d): H₆ (cis); 5.76 (m): H₇ (cis); 5.23 (m): N⁺ --CH₂; 6.24: ═CH--CH₂ (ΔE); 6.77 and 6.78 (s): H₅ thiazole; 6.85 to 7.02:aromatic and ═CH--CH═; 7.95, 8.70: pyridinium; 9.30 (sl); 9.62 (d,d);9.96 (ml): the mobile H's; 7.34: NH₂.

EXAMPLE 36 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(3-chloro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl) quinolinium

STEP A: 1-[3-[7β-[[[[[1-[3-chloro-4,5-bis-[methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3 -yl]-2-propenyl]quinolinium iodide

Using the procedure of Step H of Example 1, 900 mg of the product ofStep C of Example 34 and 0.366 ml of quinoline were reacted to obtainafter chromatography on silica (eluant: methylene chloride--methanol(97.3)), 384 mg of the desired product.

NMR Spectrum: CDCl₃ 300 MHz 3.24 s), 3.29 (s), 336 (s,d): the O--CH₃ 's;3.78 (s): φ-OMe; 3.40 (m), 3.58 (m), 3.71 (m), 4.00 (m): the central CH₂'s; 5.07 and 5.26,--CO₂ CH₂ φ and O--CH₂ --O; 4.94 (s): H₆ ; 5.04 (m),H₇ ; 6.00 to 6.20: ═CH--CH₂ --N+; 5.99 (s) resolved: φ--CH--O; 6.38 (m),6.55 (m): ═CH--CH₂ (ΔE); 6.75 (s) resolved: H₅ thiazole; 6.85 to 7.40;aromatics and ═C--CH═CH--CH₂ ; 7.91 (m), 8.08 to 826 (m), 8.42 (m), 8.95(m), 10.49 (d): quinoline and mobile H. STEP B: Internal salt of(6R,(3-(E) 6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(3-chloro-4,5-dihydroxy-phenyl)methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)quinolinium

Using the procedure of Step I of Example 1, 384 mg of the product ofStep A were reacted to obtain 192 mg of the desired product.

NMR Spectrum: DMSO 300 MHz 3.35 to 3.70: CH₂ S; 5.11 (d, J=5); 5.15 (d,J=5): H₆ ; 5.32 (o) 5.34 (s): ##STR54## 5.74 (m): H₇ : 5.89 (m):═CH--CH₂ --N; 6.36 (m): ═CH--CH₂ ; 6.75 to 7.00 (m): other CH═, aromaticand H₅ thiazole; 7.33: mobile H's, 8.07, 8.26,8.52, 9.33: quinoline;9.57, 9.29, 9.60, 9.91 (m) 13.00 (eq) 13.70 (m): mobile H's.

EXAMPLE 37 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy)-3,4-dihydroxy-2-fluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl]-quinolinium STEPA:1α-(hydroxy)-2-fluoro-(3,4-bis-[(2-methoxy-ethoxy)-methoxy]phenyl]-aceticacid

Using the procedure of Step A of Example 1, 15.5 g of2-fluoro-3,4-bis-[(2-methoxy-ethoxy]-methoxy]-benzaldehyde were reactedto obtain 20.7 g of the desired product which was used as is for thefollowing step.

STEP B: Diphenylmethyl[2-fluoro-(3,4-bis-[(2-methoxy-ethoxy]methoxy]-phenyl]-hydroxy acetate

Using the procedure of Step B of Example 1, 20.6 g of the product ofStep A and 9.08 g of diphenyl diazometane were reacted to obtain afterchromatography on silica (eluant: cyclohexane--ethyl acetate (7-3)), 3.2g of the desired product.

IR Spectrum: CHCl₃

OH 3600 cm⁻¹ and 3530 cm⁻¹

C═O 1733 cm⁻¹

Aromatics 1620, 1603, 1588, 1498 cm⁻¹

STEP C: Diphenylmethyl[2-fluoro-(3,4,bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-phthalimidoxyacetate

Using the procedure of Step C of Example 1, 3.2 g of the product of StepB were reacted to obtain after chromatography on silica, (eluant:methylene chloride--acetone (95-5)), 2.9 g of the desired product.

IR Spectrum (CHCl₃

C═O 1794, 1754, 1737 cm⁻¹

Aromatics 1619, 1597, 1498 cm⁻¹

STEP D: Diphenylmethylaminoxy-[2-fluoro-(3,4-bis-[(2-methoxyethoxy)-methoxy]-phenyl]-acetate

Using the procedure of Step D of Example 1, 1.05 g of the desiredproduct were obtained.

IR Spectrum: CHCl₃

O--NH₂ 3340 cm⁻¹

C═O 1744 cm⁻¹

starting NH₂ ⁺ 1620, 1580, 1498 cm⁻¹

Aromatic

STEP E:[[[1-[2-fluoro-(3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-[(triphenyl)-amino]-thiazol-4-ylacetic acid

Using the procedure of Step E of Example 1, 1.05 g of the product ofStep D and 0.777 g of oxo-[2-[(triphenylmethyl)-amino]-thiazol-4-ylacetic acid (Belgium Application No. 864,828) were reacted to obtain1.74 g of the desired product which was used as is for the followingstep.

STEP F:4-methoxy-benzyl7β-[[[[[1-[2-fluoro-3,4-bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy]-ethoxy]-oxy]-imino][2-(triphenylmethyl]-amino]-thiazol-4-yl]-acetamido]-3-[(Z)3-chloro-1-propenyl-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate

Using the procedure of Step F of Example 1, 1.74 g of the product ofStep E and 0.784 g of 4-methoxy-benzyl7β-amino-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylatewere reacted to obtain after chromatography on silica (eluant: methylenechloride--ethyl acetate (8-2)), 1.7 g of the desired product which wasused as is for the following step.

STEP G: 4-methoxy-benzyl7β-[[[[[1-[2-fluoro-(3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetyl]amino]-3-[(Z)-3-iodo-1-propenyl-8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-en-2-carboxylate

Using the procedure of Step G of Example 1, 840 mg of the product ofStep F were reacted to obtain 814 mg of the desired product with aRf=0.45 (CH₂ Cl₂ -ACOEt (8-2)).

STEP H:1-[3-[7β-[[[[[1-[2-fluoro-(3,4-bis-[(2-methoxy-ethoxy]methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy]-ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenylquinolinium iodide

Using the procedure of Step H of Example 1, 814 mg of the product ofStep G and 0.337 ml of quinoline were reacted to obtain afterchromatography on silica (eluant: methylene chloride--methanol (98-2)368 mg of the expected product.

NMR Spectrum: CDCl₃ 300 MHz 3.31 to 3.35: the O--CH₃ 's; 3.45 (d, J=16):CH₂ S; 3.51, 3.81, 3.94: the central CH₂ 's; 3.79 (s) 3.80 (s): the0φ--O--CH₃ 's; 4.91 (m): H₆ ; 5.15 to 5.30: CO--CH₂ φ's, O--CH₂ --O;5.83: H₇ ; 6.05 (ml): ═C--CH₂ --N+; 6.31, and 6.35 (m): the O--CH--φ's;6.49 (ml): CH₂ --CH--CH; 6.72, 6.75: H₅ thiazole; 6.87 to 7.40:aromatics, CO₂ --CHφ₂, CH═CH--C; 7.90 to 8.20: quinoline, 8.40 (d,d): H₄'; 8.90 (d,d): H₂ '.

STEP I: Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl((carboxy-(3,4-dihydroxy-2-fluoro-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl) quinolinium

Using the procedure of Step I of Example 1, 357 mg of the product ofStep H were reacted to obtain 176.9 mg of the desired product.

NMR Spectrum: DMSO 300MHz 5.14: the H₆ 's; 5.41 (s) resolved: O--CH--φ;5.70 to 5.90: CH₂ N⁺ and H₇ ; 6.54 (d, J=8.5) and 6.70 to 6.80: aromaticand H₅ thiazole; 6.37 (m): --CH═CH--CH₂ (≢E); 6.97 (d,d): --CH═CH--CH₂ ;7.34 (1): NH₂ ; 8.07 to 9.58: quinoline; 9.16, 9.49, 9.69: mobile H's.

PREPARATION OF EXAMPLE 372-fluoro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]benzaldehyde

STEP A: 2-fluoro-3,4-bis-dihydroxy-benzaldehyde

A mixture of 74.3 g of hexamethylenetetramine and 125 ml oftrifluoroacetic acid was stirred for 2 hours at 80° C. and then asolution of 34 g of 3-fluorocatechol in 130 ml of trifluoroacetic acidwas added. the mixture was stirred for 2 hours at 80° C. and for 16hours at ambient temperature. The trifluoroacetic acid was distilled atreduced pressure and the residue was taken up in water and neutralizedby the addition of potassium carbonate until a pH of 7 wa achieved.After filtration and extraction with ether, the extracts were dried andevaporated to dryness under reduced pressure to obtain 39 g of theproduct which was used as is for the following step.

STEP B: 2-fluoro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-benzaldehyde

261 ml of N-ethyl diisopropylamine were added to a solution of 39 g ofthe product of Step A in 390 ml of acetonitrile and the mixture wascooled to -5° C. 113 ml of (2-methoxyethoxy) methyl chloride were addedslowly and the mixture was stirred for 16 hours at -5° C. Theacetonitrile was evaporated and the residue was taken up in 250 ml ofmethylene chloride, then washed with N hydrochloric acid, with water,with N sodium hydroxide and then with water, followed by drying,filtering and evaporating to dryness under reduced pressure to obtain49.5 g of product which was chromatographed on silica (eluant: methylenechloride--acetone (96-4)) to obtain 10.4 g of the desired product.

NMR Spectrum: CDCl₃ 200 MHz 3.37, 3.38 (s): the OCH₃ 's; 5.24 (s); 5.37(s): the O--CH₂ --O's; 3.56 (m), 3.83 (m), 4.00 (m): the central CH₂ 's;10.26 (s): CHO; 7.03 (dd J=1.5-9): H₄ ; 7.59 (dd J=7.5-9): H₃.

EXAMPLE 38 Internal salt of (6R-(3-(E)6α,7β(Z)))-1-[3-(7-(((2-amino-4-thiazolyl)(carboxy-(3,4-dihydroxy-2-fluorophenyl)-methoxy)-imino)acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo (1,2a)pyridinium

STEP A:1-[3-[7β-[[[[[1-[2-fluoro-(3,4-bis-[(2-methoxy-ethoxy)methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]2-[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl-imidazo(1,2-a)pyridiniumiodide

Using the procedure of Step H of Example 1, 704.5 g of the product ofStep G of Example 37 and 0.25 ml of imidazo(1,2-a) pyridine were reactedto obtain after chromatography on silica (eluant: methylenechloride--methanol (95-5), 275 mg of the expected product.

NMR Spectrum: CDCl₃ 400 3.32, 3.33 (s); the --OCH₃ 's; 3.46, 3.47 (d):CH₂ S; 3.78 (m): the o--O--CH₃ 's; 3.53, 3.81, 3.95: the central CH₂ 's;4.82: H₆ ; 5.78: H₇ ; 5.00 to 5.32: OCH₂ O--, CO₂ CH₂ φ, ═CH--CH₂ N⁺ ;5.40: the other H of CH₂ N⁺ ; 6.32, 67.37 (s): O--CH--φ; 6.28 (m): CH₂--CH═CH (ΔE); 6.74 (s), 6.76 (s): H₅ thiazole; 6.8 to 7.40: oC, COCH₂--o₂, aromatic, ═CH--CH═CH (ΔE); 7.84 (m) to 9.13 (5H) imidazopyridinium.

STEP B: Internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(3,4-dihydroxy-2-fluoro-phenyl)methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo(1,2-a)pyridinium

Using the procedure of Step I of Example 1, 275 mg of the product ofStep A were reacted to obtain 116.2 mg of the desired product.

NMR Spectrum: DMSO 300 MHz 3.60: CH₂ S; 5.11, 5.14 (d): H₆ ; 5.75 (dd)5.79 (dd): H₇ ; 5.30 (m): CH₂ N⁺ ; 5.64, 5.65 (s): O--CH--φ6.25 (m):CH═CH--; 6.91, 6.93 (d): CH═CH--CH₂ ; 6.57, 6.74 (m): H₅ " and H₆ ";6.77 (s) 6.79 (s): H₅ thiazole; 7.57, 8.05 (dd): H₅ ' and H₆ '; 8.22 (d)8 98 (dd): H₄ ', H₇ '; 8.30 8.46 (m): H₂ ', H₃ '; 9.48 (d) 9.55 (d):CH--NH--C═O; 7.32, 9.13, 9.64 (m): mobile H's.

EXAMPLE 39 Internal salt of (6R-C3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,5-difluoro-3,4-dihydroxyphenyl)-methoxy)imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo(1,2-a) pyridinium

STEP A: Diphenylmethyl [2,5-difluoro-3,4-bis-dihydroxy]-phenyl-hydroxyacetate

Using the procedure of Step B of Example 1, 3.30 g of[2,5-difluoro-3,4-bis-dihydroxy]-phenyl hydroxy acetic acid and 2.77 gof diphenyl diazomethane were reacted to obtain after chromatography onsilica (eluant: cyclohexane--acetone (6-4)), 3.75 g of the desiredproduct.

IR Spectrum:

Complex absorptions OH/NH region

C═O 1752 cm⁻¹

Aromatic 1630-1535-1485 cm⁻¹

STEP B: Diphenylmethyl[2,5-difluoro-3,4-bis-[(2-methoxy-ethoxy)-methoxy)-phenyl]-hydroxy-acetate

2.96 g of diisopropylethylamine and 10 ml of methylene chloride wereadded to a solution of 4.21 g of the product of Step A in 45 ml ofmethylene chloride and the mixture was cooled to -5° C. 2.71 g ofmethoxy-ethoxymethyl chloride and 5 ml of methylene chloride were addedslowly and the mixture was stirred for 30 minutes at -5° C. and pouredinto 30 ml of 0.1N hydrochloric acid. The mixture was decanted andwashed with a saturated solution of sodium bicarbonate (pH 8), drying,filtering and concentrating to dryness under reduced pressure to obtain6.9 g of product which was chromatographed on silica (eluant: methylenechloride--ethyl acetate (85-15)) to obtain 3,577 g of the desiredproduct.

IR Spectrum: CHCl₃

approx. 3600 cm⁻¹ (f)-3530 cm⁻¹ complex: OH

1734 cm⁻¹ : C═O

1624-1600-1589-1492 cm⁻¹ : aromatic.

NMR Spectrum 19_(F)

140 6 F², J_(F1-F4) =14, J_(F1H5) =6.5

135.2 F⁵, J_(F4-H5) =11.

STEP C: Diphenylmethyl2,5-difluoro-3,4-bis-[(2-methoxy-ethoxy)-methoxy)-phenyl]-phthalimidoxyacetate

Using the procedure of Step C of Example 1, 4,419 g of product of Step Band 1.41 g of hydroxyphthaliide and 4.12 g of triphenyl-phosphine werereacted to obtain after chromatography on silica (eluant: methylenechloride--acetone (97-3) then cyclohexane --ethyl acetate (1-1)), and2.56 g of the desired product.

NMR Spectrum: CDCl₃ 300 MHz 3.33 (s), 3.36 (s): OCH₃ ; 3.50 (m), 3.91(m): O--CH₂ --CH₂ --O; 5.20 (A,B system), 5.26 (A,B system): OCH₂ O;6.26 (s): ##STR55## 6.94 (s): CO₂ CH Ph₂ --; 7.15, 7.3 (m); 7.76 (m):aromatic H's.

STEP D: Diphenylmethylaminoxy-[2,5-difluoro-3,4-bis-[(2-methoxy-ethoxy)-methoxy)-phenyl]-acetate

Using the procedure of Step D of Example 1, 2.537 g of the product ofStep C and 0.21 ml of hydrazine hydrate were reacted to obtain afterchromatography on silica (eluant: cyclohexane--ethyl acetate (1-1)),1.67 g of the desired product is obtained.

NMR Spectrum ¹⁹ F: CDCl₃

135.5 (dd) F₅

139.8 (dd) F₂

J_(F5-F2) =14

J_(F5-H6) =10.5

J_(F2-H6) =6

STEP E:[[[1-[2,5-difluoro-3,4-bis-[(2-methoxy-ethoxy)-methoxy)phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-[(triphenylmethyl)-amino]-thiazol-4-yl]aceticacid

Using the procedure of Step E of Example 1, 909 mg of the product ofStep D and 652 mg ofoxo-[2-[(triphenylmethyl)-amino]thiazol]-4-yl]-acetic acid BelgianApplication No. 864,828) were reacted to obtain after chromatography onsilica (eluant: methylene chloride--methanol (96-4)), 1.138 g of thedesired product is obtained.

IR Spectrum:

═C--NH+approx. 3405 cm⁻¹

general absorption OH/NH

C═O 1740 -1727 cm⁻¹

C═N

Aromatic +1615 -1597 -1526 -1495 cm⁻¹

Heteroaromatic

STEP F: 4-methoxy benzyl7β-[[[[[1-[2,5-difluoro-3,4-bis[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino][2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetyl]-amino]-3-[[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2 -en-2-carboxylate

Using the procedure of Step F of Example 1, 1.12 g of the product ofStep E were reacted to obtain after chromatography on silica (eluant:methylene chloride--ethyl acetate (9-1)), 979 mg of the expectedproduct.

NMR Spectrum: CDCl₃ 400 MHz 3.08, 3.20, 3.40: CH₂ S; 3.34, 3.35 (s): theC--O--CH₃ 's; 3.54, 3.92 (m): the central CH₂ 's; 3.80, 3.81 (s):Ar--O--CH.sub. ; 3.70, 4.00: CH═CH₂ Cl; 4.95, 5.03: H₆ cephalo; 5.16,5.25:OCH₂ O, CO₂ CH₂ Ar; 5.75 (m): ═CH--CH₂ (ΔZ); 5.85, 6.00: H₇cephalo, ═CH--CH₂ ; 6.26 (d, J=11) 6.35 (m): C--CH═CH--CH₂ Cl , ArCHO;6.70, 678 (m): H₅ thiazole; approx. 7.00 to 7.35: aromatic H's; 7.80,8.30: NH--CH.

STEP G: 4-methoxy-benzyl7β-[[[[[1-[2,5-difluoro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate

Using the procedure of Step G of Example 1, 969 mg of the product ofStep F were reacted to obtain 725 mg of the expected product.

STEP H:1-[3-[7β-[[[[[1-[2,5-difluoro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxy-benzyloxy]-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-imidazo(1,2-a)pyridiniumiodide

Using the procedure of Step H of Example 1, 717 mg of the product ofStep G and 313 mg of imidazo (1,2-a)pyridine were reacted to obtainafter chromatography on silica (eluant: methylene chloride --methanol(95-5)), 350 mg of the desired product.

NMR Spectrum: CDCl₃ 400 MHz 3.32, 3.33, 3.34 (s): C--O--CH₃ ; 3.53, 3.92(m): central CH₂ 's; 3.30, 3.80: CH₂ S; 3.79, 3.80 (s): Ar--O--CH₃ ;4.94 (dd): H₆ cephalo; 5.80, 5.88 (d) after exchange: H₇ cephalo; (td);6.31 (td): ═CH--CH₂ N⁺ ; 6.31 (s) 6.37 (s): Ar--CH--CO₂ ; 7.84, 8.18(d): CO--NH--CH; 7.86, 8.02 (m): heterocycle; 8.32 to 9.18:imidazopyridine; 6.75, 7.45 (m): aromatic, H₅ thiazole, CH--CH--CH₂, CO₂--CH--φ₂ ; 5.18, 5.30, 5.43: CH₂ --N⁺, OCH₂ O, ##STR56##

STEP I: Internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,5-difluoro-3,4-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo (1,2-a) pyridinium

Using the procedure of Step I of Example 1, 344 mg of the product ofStep H were reacted to obtain 170 mg of the expected product.

NMR Spectrum: DMSO 300 MHz

5.16 (dd):L H₆ cephalo; 5.77 (m): H₇ cephalo; 5.29 (m): CH₂ --N⁺ ;(s,d): ##STR57## 6.70 (dd): aromatic H coupled with 2F: 6.80 (s,d): H₅thiazole; 6.87 (dd) CH═CH--CH₂ (ΔE): 7.33 (sl): NH₂ ; 8.28, 8.44 (m): H₂' and H₃ '; 7.18 to 8.96 (4H) imidazopyridine; 9.03, 9.63 (d):C--NH--CH; 9.84 other mobile H's.

PREPARATION OF EXAMPLE 39 2,5-difluoro-3,4-dihydroxy]-phenylhydroxy-acetic acid

STEP A: 2,5-difluorophenol

325 ml of n-butyl lithium in a 1.6M solution with hexane were added at-65° C. to a solution of 62.19 g of 1,4-difluorobenzene in 500 ml oftetrahydrofuran and the mixture was stirred for 150 minutes. Then, asolution of 53.8 g of trimethylborate in 250 ml of ether was added over30 minutes at -65° C. and the mixture was stirred for 90 minutes,allowing the temperature to rise to -15° C. The mixture was stirred for15 minutes and 350 ml of 10% hydrochloric acid were added. Afterdecanting, the residue was washed with water, dried and evaporated todryness under reduced pressure to obtain 63.5 g of product which wastaken up in 400 ml of toluene. After heating to 108° C., 180 ml of 30%hydrogen peroxide were added dropwise and heating was continued for 2hours at 90° C. The medium was allowd to cool and was filtered. Thefiltrate was decanted and the organic phase was washed with water, thenwith a 10% solution of ferrous ammonium sulfate, then with water. Theorganic phase was extracted twice with 300 ml of 2N sodium hydroxide andacidification was carried out with concentrated hydrochloric acid,followed by extraction with methylene chloride. The extracts were driedand evaporated to dryness under reduced pressure to obtain the desiredproduct.

NMR Spectrum: CDCl₃ 5.21 (sl): OH; 6.55 (dddd): H₄, JH₄ -H₂ =9, JH₄ -F₂=3.5, JH₄ -H₆ =3, JH₄ F₅ =8; 6.74 (ddd): H₆, JH₆ -H₄ =3, JH₆ -F₂ =7;7.01 (ddd); H₃, JH₃ H₄ =9, JH₃ -F₂ =10, JH₃ -F₅ =5.

STEP B: 2,5-difluoroanisole

35.0 g of the product of Step A, 350 ml of acetone, 44.6 g of potassiumcarbonate and 40.7 g of dimethyl sulfate (neutralized on potassiumbicarbonte) and was allowed to returnto ambient temperature. Water wasadded and extraction was carried out with ether. The extracts werewashed, dried and concentrated to dryness under reduced pressure toobtain 39.8 g of the desired product.

NMR Spectrum: ¹⁹ F CDCl₃ 188 MHz

119.1 (dddd) F₅

144.1 (dddd) F₂ JF₂ -F₅ =15

J_(F5-H3) =5 J_(F2-H3) =10.5

J_(F2-H4) =8 J_(F2-H4) =3.5

J_(F5-H6) =10 J_(F2-H6) =7

STEP C: 3,6-difluoroguaiacol

Using the procedure of Step A, 55.15 g of the product of Step, B and 220ml of n-butyl lithium, 1,6M in hexane, 36.4 g of trimethyl borate and200 ml of 30% hydrogen peroxide were reacted to obtain 44.7 g of thedesired product.

NMR Spectrum: CDCl₃ 200 MHz

4.02 (d, J=2) OCH₃

5.56 (sl) OH

6.57 (ddd ) H₄

6.75 (dt) H₅

J_(H5-H4) =9.5; J_(H5-F-6) =9.5; J_(H4-F3) =10.5; J_(H4-F6) =5.

STEP D: 3,6 difluorocatechol

Using the procedure of Step B of Preparation 1, 21.15 g of the productof Step C and 260m 1 of a molar solution of boron tribromide werereacted to obtain 17.62 g of the desired product.

STEP E: 2,5-difluoro-3,4-dihydroxy]-phenyl-hydroxy-acetic acid

7.69 g of sodium hydroxide dissolved in 80 ml of water were added at+10° C. to a solution of 11.7 g of the product of Step D and 7.37 g ofmonohydrated glyoxylic acid in 40 ml of water and the mixture wasstirred for 30 minutes at 10° C. then for 3 hours 30 minutes at ambienttemperature. 0.74 g of monohydrated glyoxylic acid were added and themixture was stirred for one hour at ambient temperature. Concentratedhydrochloric acid was added until a pH of 1 was achieved. Extraction wascarried out with ethyl acetate, and the extracts were dried, filteredand concentrated to dryness under reduced pressure to obtain 17.0 g ofthe desired product.

IR Spectrum: Nujol

Complex absorption OH/NH region

C═O 1700 cm⁻¹

Aromatic 1640, 1612, 1526, 1488 cm⁻¹

EXAMPLE 40 Internal salt (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2-chloro-4,5-dihydroxy-3-methoxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl]-imidazo(1,2-a) pyridinium

STEP A:[2-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-3-methoxy]benzaldehydeand 2-chloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-5-methoxy benzaldehyde

2.17 g of 3,4-bis-[(2-methoxy-ethoxy)-methoxy]-5-methoxy benzaldehydeand 21.7 ml of methylene chloride and 4 ml of a solution of 1.76 g ofcalcium hypochlorite (at 65%) in 10 ml of water were stirred for 20minutes at 0° to +5° C. Extraction was carried out with methylenechloride and the extracts were washed with water, dried and evaporatedto dryness under reduced pressure to obtain 2.34 g of a mixture ofisomers (7/3)

NMR Spectrum: CDCl₃ 250 MHz 3.37: the OCH₃ 's; 3.7 to 4.1: the centralCH₂ 's; 5.29 to 5.33: OCH₃ ; 3.91: OCH₃ ; 7.54 and 7.30: H₆ ; 10.38 and10.40: CHO.

STEP B: [2-chloro-4,5-bis-[(2-methoxy-ethoxy)-methyl]-3-methoxy-styrylcarboxylate and corresponding 5-methoxy isomer

2.97 ml of triethylamine, then a solution of 6.72 g of the mixture ofisomers of Step A dissolved in 60 ml of tetrahydrofuran were added to astirred mixture, a +5° to +10° C. of 2.162 g of lithium bromide with 60ml of tetrahydrofuran and 4.03 ml of triphenylphosphoro-acetate. Themixture was stirred for 16 hours at ambient temperature and concentratedto dryness under reduced pressure. The residue was taken up in methylenechloride, washed with 1N hydrochloric acid, then with water, dried andevaporated to dryness under reduced pressure to obtain 8.9 g of theexpected product (mixture of 2 isomers 7/3).

NMR Spectrum: CDCl₃ 250 MHz 1.35 (t,d) 4.28 (q,d): CO₂ Et; 3.37, 3.38:the OCH₃ 's; 3.57 (m); 3.84 to 4.04 (m): the central CH₂ 's; 3.88 (s);3.86 (s): OCH₃ ; 5.24 to 5.28: the OCH₂ 's; 6.34 (d), 6.38 (d):CH═CH--CO₂ ; 8.03, 8.05 (d): --CH═CH--CO₂ ; 6.93, 7.30: aromatic H.

STEP C: [2-chloro-4,5-bis-[(2-methoxy]-ethoxy)-methoxy]-3-methoxy]styrol andcorresponding 5-methoxy isomer

11.7 ml of a molar solution of diisobutyl aluminium hydride in hexanewere added to a solution cooled to -70° C. of 2.83 g of the isomermixture of Step B in 20 ml of methylene chloride. The mixture wasstirred for 20 minutes, at -70° C. and 2 ml of water were added Themixture was stirred for 30 minutes at 20° C. followed by drying,filtering and evaporation to dryness under reduced pressure to obtain1.95 g of the desired product (mixture of isomers 7/3)

NMR Spectrum: CDCl₃ 250 MHz 3.37, 3.38: the OCH₃ 's; 3.54, 3.84, 3.97(m): the central CH₂ 's; 3.87 (s): OCH₃ (in position 3); 4.34 (d): --CH₂--OH; 6.29 (t): CH═CHCH₂ ; 6.93 (d): --CH═CH--CH₂ ; 7.19 (s): aromaticH.

STEP D:[2-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-3-methoxy](1,2-epoxy)styrol (isomer A) and [2-chloro-3,4-bis-[C 2-methoxy-ethoxy)-methoxy]-5-methoxy](1,2-epoxy) styrol (isomer B)

A solution of 2.79 g of m-chloroperbenzoic acid in 50 ml of methylenechloride was added at +5° C. to a solution of 4.78 g of the isomermixture of Step C in 50 ml of methylene chloride and the mixture wasstirred for 16 hours at 20° C. 20 ml of a saturated solution of sodiumbicarbonate and 50 ml of methylene chloride were added, followed bydecanting, washing with water, drying and evaporting to dryness underreduced pressure. The residue was chromatographed on silica (eluant:methylene chloride--acetone 85-15) to obtain 2.12 g of isomer A productand 716 mg of isomer B.

NMR Spectrum: CDCl₃ 250 MHz 3.07 (t,d): ##STR58## 3.37, 3.38 (s): theOCH₃ 's; 3.57, 3.83, 3.93 (m): the central CH₂ 's; 3.88 (s): OCH₃ (inposition 3); 3.83, 4.06 (ddd): --CH₂ OH; 4.19 (d, J=2): ##STR59## 5.2,5.26 (s): the OCH₂ 's; 1.94 (d,d, J=5.5, 7.5): OH.

STEP E: Diphenylmethyl [[2-chloro-4,5-bis-[(2-methoxy-ethoxy) methoxy]-3-methoxy]-phenyl]-chloroacetate

a) Opening of the epoxide

A solution prepared at +5° C. of 1.306 g of copper chloride, 20 ml oftetrahydrofuran and 1 g of lithium chloride was stirred for 5 minutesand then, 2.055 g of the isomer A epoxid of Step D dissolved in 10 ml oftetrahydrofuran were added to this solution at 20° C. The mixture wasstirred for 5 hours at 20° C. and 10 ml of water were added, followed bydecanting, washing, drying and evaporating to dryness under reducedpressure to obtain 2.09 g of intermediate diol.

b) Oxidation

9 ml of water and 3.79 g of sodium periodate and 50 mg of hydratedruthenium chloride (with 35/40% Ru) were added at +5° C. to +10° C. to asolution fo 2.035 g of the diol above with 6 ml of, carbon tetrachlorideand 6 ml of acetonitrile. The mixture was stirred for one hour at 20° C.and 20 ml of methylene chloride and 10 ml of water were added, followedby decanting, washing, drying and evaporating to dryness under reducedpressure to obtain 1.8 g of the intermediary acid.

c) Esterification:

790 mg of diphenyl diazomethane were added to a solution of 1.8 g of theabove product in 20 ml of methylene chloride and the mixture was stirredfor one hour at 20° C. and concentrated to dryness under reducedpressure. After chromatography on silica (eluant: methylene chloride(9-1)), 1.525 g of the desired product was obtained.

NMR Spectrum CDCl₃ 250 MHz 3.34, 3.37: the OCH₃ 's; 3.47, 3.57, 3.74,3.97 (m): the central CH₂ 's; 3.87 (s): 3-methoxy; 5.12, 5.24: the OCH₂'s; 5.94: ##STR60## 6.89 (s): CO₂ --CH

STEP F: Diphenylmethyl aminoxy-[[2-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-3-methoxy]-acetate

a) Phthalimidoxylation

1.48 g of the product of Step E, 7.5 ml of dimethylformamide with 363 mgof potassium acetate and 604 mg of N-hydroxyphthalimide were stirredtogether for 5 hours.

b) Hydrazinolysis

180 μl of hydrazine hydrate were added at 20° C. and after the mixturewas stirred for 20 minutes at 20° C., the phthalylhydrazide wasseparated out and washed with acetonitrile. The organic fractions wereevaporated to dryness to obtain after chromatography on silica (eluant:methylene chloride--ethyl acetate (3-1)), 1.11 g of the desired product.

NMR Spectrum: CDCl₃ 250 MHz 3.33, 3.37 (s): the OCH₃ 's; 3.44, 3.57,3.71, 3.97 (m): the central CH₂ --s; 3.88 (s): 3 -methoxy; 5.09 and5.23: the OCH₂ 's; 5.73 (s): ##STR61## 5.84: NH₂ ; 6.91 (s); 6.94: CO₂CH-o₂ ; 7.07 to 7.35: aromatics.

STEP G:[[[1-[2-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-3-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-[(triphenylmethyl]-amino]-thiazol-4-yl]-aceticacid

Using the procedure of Step E of Example 1, 1.1 g of the product of StepF and 835 mg of oxo-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-aceticacid (Belgian Application No. 864,828) were reacted. The product was notisolated and was used as is for the following step.

STEP H: 4-methoxy-benzyl7β-[[[[[1-[2-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-3-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethoxy]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2 -carboxylate

Using the procedure of Step F of Example 1, the crude product of Step Gand 781 mg of 4-methoxy-benzyl7β-amino-3[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylatehydrochloride (EP 0,333,154) were reacted to obtain after chromatographyon silica, (eluant: methylene chloride--ethyl acetate (9-1)), 1.36 g ofthe desired product.

NMR Spectrum: CDCl₃ 300 MHz 3.25, 3.29, 3.36, 3.37, 3.81: the OCH₃ 's;3.20 to 4.0: --SCH₂ --, C--CH₂ Cl, the central CH₂ 's; 4.94 (d) to 5.25:CO₂ CHφ₂, NH--CH--CH--S, the OCH₂ O's; 5.75 (m): --CH═CH--CH₂ (Z); 5.9(m): NH--CH--CH--S; 6.28 (d): --CH═CH--CH₂ (ΔZ); 6.8 to 7.15: aromatics+H₅ thiazole.

STEP I: 4-methoxy-benzyl7β-[[[[[1-[2-chloro-4,5-bis-[(2-methoxy-ethoxy]-methoxy]-3-methoxy]phenyl]-2-oxo-2-(diphenyl-methoxy)ethyl]oxy]-imino][2(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate

Using the procedure of Step G of Example 1, 1.33 g of the product ofStep H were reacted to obtain after chromatography on silica (eluant:methylene chloride--ethyl acetate (9-1)), 990 mg of the desired product.

NMR Spectrum: CDCl₃ 400 MHz 3.24 (s); 3.26 (s); 3.35 (s); 3.36 (s): the2 OCH₃ 's; 3.2 to 4.0 (m): --SCH₂ --C and the central CH₃ 's; 3.8 (s,d)3.85, 3.88 (s): the 2 ═C--OCH₃ 's; 4.9 to 5.07 (m) 5.18 to 5.25 (m): theO--CH₃ 's; 4.97, 5.02 (d): CH--CH--S--; 5.87 (ddd) NH--CH--CH--S--;6.51, 6.53 (s): ═NH--O--CH═; 6.79, 6.80 (s): H₅ thiazole; 6.84 to 7.37(m): aromatics other CH═C and CO₂ --CH--φ₂ ; 7.78, 8.3 (d): ##STR62##

STEP J:1-[3-7β-[[[[[1-[2-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-3-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]acetamido]-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-imidazo (1,2-a) pyridinium iodide

Using the procedure of Step H of Example 1, 735 mg of the product ofStep I and 260 microliters of imidazo(1,2-a)pyridine were reacted toobtain 750 mg of the expected product.

NMR Spectrum: CDCl₃ 300 MHz 3.14 to 3.38: --S--CH₂ --C═, the ##STR63##3.78, 3.79, 3.85, 3.87: ═C--OCH₃ ; 2.3 to 4.0: the central CH₂ 's; 4.9to 5.02: NH--CH--CH--S--; 5.8 (m): ═NH--CH--CH--S; 6.27 (m):--CH═CH--CH₂ (ΔE); 6.53, 6.54: ##STR64## 6.76 to 7.3: CO₂ --CH--φ₂,--CH═CH--CH₂ and the aromatics; 7.6 to 91.0: imidazopyridine.

STEP K: Internal salt of [6R-[3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2-chloro-4,5-dihydroxy-3-methoxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo(1,2-a)pyridinium

Using the procedure of Step I of Example 1, 750 mg of the product ofStep J were reacted to obtain 463 mg of the desired product.

NMR Spectrum: DMSO 300 MHz 5.12 (d,d): ═NH--CH--CH--S--; 528 to 5.3:═CH--CH₂ --N⁺ ; 5.74 (m): ═NH--CH--CH--S; 5.75: ═N--O--CH--; 6.23 (m):═C--CH═CH--; 6.78 (s): H₅ thiazole; 6.84 (d, J=15): ═C--CH═CH-- (ΔE);7.36: NH₂ ; 7.58 to 8.93: imidazopyridine; 9.55: mobile H's.

EXAMPLE 41 Internal salt of (6R-(3-(E) 6α,7β(Z)))-1-(3(7-(((2-amino-4thiazolyl)(carboxy-(2-chloro-3,4-dihydroxy-5-methoxy-phenyl)-methoxy)-imino)-acetyl)-amino)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl)-imidazo(1.2-a) pyridinium

Using the procedure of Steps E to K of Example 40, isomer B of Step D ofExample 40 were reacted to obtain the desired product.

NMR Spectrum: DMSO 300 MHz 3.5 to 3.7 (m): S--CH₂ --C═; 3.73, 3.74 (s):OCH₃ ; 5.18: NH--CH--CH--S; 5.29: --CH₂ CH--; 5.79 (ddd): NH--CH--CH--;--CH N⁺ 5.83, 5.85 (s): ═N--O--CH═; 6.25 (m): CH═CH--; 6.6 (s): 6.78(s): 6.82 (s): aromatic, H₅ thiazole; 6.88 (d, d J=16 ): --CH═CH--CH₂(ΔE); 7.58 to 8.96 96H) imidazopyridine.

EXAMPLE 42 Internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2-chloro-4,5-dihydroxy-3-methoxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)quinolinium

STEP A:1-[3-[7β-[[[[[1-[2-chloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-3-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido1-2-[(4-methoxy-benzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]quinoliniumiodide

Using the procedure of Step J of Example 40, 700 mg of the product ofStep I of Example 40 and 282 microliters of quinoline were reacted toobtain 706 mg of the desired product.

STEP B: Internal salt of (6R-(3-(E) 6 amino-4-thiazolyl)(carboxy-(2-chloro-4,5-dihydroxy-3-methoxy-phenyl)-methoxy)-imino)-acetamdio)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)quinolinium

Using the procedure of Step K of Example 40, 690 mg of the product ofStep A were reacted to obtain 434 mg of the desired product.

NMR Spectrum: DMSO 300 MHz 3.4 to 3.8 (m): S--CH₂ --; 3.65, 3.73 (s):═C--OCH₃ ; 5.1, 5.14 (d): --NH--CH--CH--; 5.73: --NH--CH--CH--; 5.75(s): ═N--O--CH═; 5.89 (m): --CH--CH--CH₂ ; 6.75, 6.76, 6.78, 6.79 (s):H₅ thiazole, aromatic H; 6.35 (m): --CH═CH--C (ΔE ); 6.97 (d1 J=16):--CH═CH--C (ΔE); 8.07 to 9.58 (7H) quinoline; 9.53: --NH--CH--CH--;7.35, 9.24, 13.0: mobile H's.

EXAMPLE 43 Internal salt of(6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2-chloro-3,4-dihydroxy-5-methoxy-phenyl]methoxy)-imino-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo [4,2,0]oct-2-en-3-yl)-3-propenyl)quinolinium

STEP A:1-[3-(7β-[[[[[1-[2-chloro-3,4-dihydroxy-5-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-(triphenylmethyl)-amino]-thiazol]-4-yl]-acetamido]-2-[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]quinoliniumiodide

Using the procedure of Step J of Example 40, 450 mg of the product ofStep E of Example 41 were reacted to obtain 440 mg of the desiredproduct.

STEP B: Internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2-chloro-3,4-dihydroxy-5-methoxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)quinolinium

Using the procedure of Step K of Example 40, 440 mg of the product ofStep A were reacted to obtain 256 mg of the desired product.

NMR Spectrum: DMSO 300 MHz 3.48 to 3.84 (m): S--CH₂ ; 3.71, 3.73 (s):═C--OCH_(3;) 5.17 (d,d): --NH--CH--CH--C; 5.8 (m): --NH--CH--CH--; 5.82,5.84 (s): N--O--CH═; 5.88 (m): --CH═CH--CH₂ --; 6.38 (d, m): CH═CH--CH₂; 6.97 (d,d) (dJ=16): --CH═CH-- (ΔE); 6.59 (s): 6.77 (s): 6.81 (s): H₅thiazole, aromatic; 8.06 to 9.58: quinoline (7H); 9.53, 934 (d):C--NH--; 7.54 (m): 9.25 (m): 13.70 (m): mobile H's.

EXAMPLE 44 Internal salt of (6R-(3-(E)6α,7β-Z(S*)))-1-(3-(7-([(2-amino-4-thiazolyl)(carboxy-(3,4-dihydroxy-5-fluorophenyl)-methoxy)-imino)acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2propenyl)quinolinium

10 mg of the product of Example 3 were chromatographed on aMICROBONDAPACK C₁₈ column (eluant: water (at pH 2.7 with trifluoroaceticacid)--acetonitrile containing 0.025% trifluoroacetic acid 86-14 toobtain 1.5 mg of the expected (S) isomer and 1.5 mg of (R) isomer.

NMR Spectrum: DMSO 400 MHz 3.40 to 3.60 (m): CH₂ S; 5.13 (d, J=5): H6;5.77 (dd, J=5 and 8): H? (d after exchange); 5.32 (s) φ--CH--O; 5.87(m): CH₂ N⁺ ; 6.31 (m): CH═CH--CH₂ ; 7.00 (d, J=16): CH═CH--CH₂ ; 6.77(s): H₅ thiazole; 6.72 (m): H₄ ', H₆ '; 7.25 (s): mobile 2H's; 8.06 (dd,J=7 and 8) and 8.28 (ddl) J=7 and 9): H₆ ", H₇ ', 8.22 (dd J=6 and 8):H₃ "; 8.50 (d, J=8) and 8.55 (d, J=9): H₄ " and H₅ "; 9.33 (d, J=8): H₈"; 9.57 (d, J=6): H₂ ".

EXAMPLE 45 Internal salt of(6R-(3-(E)6α,7β-(Z(R*))]-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(3,4-dihydroxy-5-fluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)2-propenyl) quinolinium

R isomer isolated during the chromatography in Example 44.

NMR Spectrum: DMSO 400 MHz 3.39 to 3.75 (m): CH₂ S; 5.16 (d, J=5): H₆ ;5.32 (s) o--CH--O; 5.74 (dd, J=5 and 8); H? ; 5.88 (m): CH₂ N+; 6.36(dt): CH═CH--CH₂ ; 6.99 (d, J=16): CH═CH--CH₂ ; 6.73 (m) (3H): H₅thiazole and H₂ ' and H₆ '; 7.26 (s): mobile 2H's; 8.07 (t, J=8) and8.28 (t, J=8): H₆ " and H₇ "; 8.22 (dd, J=6 and 8): H₃ "; 8.50 (d, J=8)and 8.55 (d, J=9): H₅ " and H₄ "; 9.33 (d, J=8): a; 9.59 (d, J=6): H₂ ";9.59 (d, m): CONH--CH; 9.14 (s): mobile 1H.

EXAMPLE 46 Internal salt of [[6R-[3-(E)6α,7β(Z)(S*)-1]]-1-[3-7-[[(2-amino-4-thiazolyl)(carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-4-(methylthio) pyridiniumcorresponding to resolved isomer of the compound of Example 14

NMR Spectrum: DMSO 300 MHz 2.71 (s): φ-SMe; approx 3.57: ═C--CH₂ S; 5.15to 5.25: H₆ and N+--CH₂ --CH═; approx. 5.80 (sl): O--CH--o and H₇ ; 6.25(m): ═CH--CH₂ ; approx. 6.98 (d): ═C--CH═CH; 6.81 (s): H₅ thiazole;7.00: H₆ ; 7.32 (1) 2H: NH₂ ; 7.96, 8.70 (d): H pyridine; 9.58 (d):C-NH--CH; 9.84 (s) 9.92 (s): the OH's; 13.28, 13.78: the other mobileH's

EXAMPLE 47 Internal salt of (6R-(3-(E)6α,7β-(Z)(S*)))-1-(3-(7-(((2-amino-4-thiazolyl)(crboxy-(2,5dichloro-3,4-dihydroxy-phenyl)-methxoy)imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl)-imidazo(1,2-a)pyridinium

NMR Spectrum DMSO 300 MHz 5.15 (d, J=5): H6; 5.29 5 (m): CH₂ --N+; 5.79(s): O--CH-- ; 5.79 (dd, d after exchange): H₇ ; 6.24 (dt, J=15.5 and6.5): --CH--CH₂, approx. 3/4 H; 6.81 (s) 6.99 (s): H₅ thiazole, aromatic1H; 6.86 (d, J=15.5) ═C--CH═CH; 7.58 (t): 8.06 (t): H₅ ', H₆ '; 8.20(d):H₇ '; 8.96 (d): H₄ '; 8.28 (d): 8.44 (d): H₂ ', H₃ '; 9.56 (d):CH--NH--CO; 7.35 (m): approx. 2H; 9.87 (sl): 1H; 9.96 (sl): 1H; mobileH.

EXAMPLE 48 Internal salt of(6R-(3-(E)6α,7β-(Z)(R*)))-1-(3-(7-(((2-amino-4-thiazolyl](carboxy-(2,5-dichloro-3,4-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo[1,2-a-)pyridiniumium

NMR Spectrum: DMSO 300 MHz 5.15 (d, J=5): H₆ ; 5.27 (m): CH₂ --N+; 5.78(d, J=5): H₇ ; 5.81 (s): O--CH--φ approx 17 H; 6 24 (dt, J=16 and 6):═CH--CH₂, approx. 0.85 H; 6.84 (s): 6.99 (s): approx. 1.7 H, H₅ andaromatic 1H; 6.85 (d, J=16): ═C--CH═CH; 7.57 (dd, J=6 and 7): H₅ '; 8.05(dd, J=7 and 8.5): H₆ '; 8.17 (d, J=8.5): H₇ '; 8.94 (d, J=6): H₄ ':8.26 (d, J=2): 8 42 (d, J=2): H₂ ', H₃ '.

Using the procedure described in the previous examples and starting withappropriate intermediates the following products were obtained:

EXAMPLE 49 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,3-dihydroxy-4-methoxy-phenyl)-methoxy)imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2en-3-yl)-2-propenyl)quinolinum

NMR Spectrum DMSO 300 MHz 3.52 (d) 3.70: CH₂ S; 3.72, 3.74: C--OMe; 5.15(d, resolved): H₆ ; 5.57 (dd) 5.80 (m): H₇ ; 5.83, 5.87: ##STR65## 5.70to 6.0: CH₂ --N+; 6.42 (d, resolved): 6.75 (d, resolved) aromatic H;6.40 (m) 6.99 (d, resolved, J approx. 16): ethylene (ΔE) ; 6.78, 6.82:H₅ thiazole; 8.07 (t): 8.26: aH₃ ', H₆ ', H₇ '; 8.53 (d): 8.56 (d): 9.34(d): H₄ ', H₅ ', 9.53 (d): H₈ '; 9.45 (d): 9.56 (d): ##STR66## 7.45 and8.84: mobile H.

EXAMPLE 50 Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4thiazolyl(carboxy-(2,3-dihydroxy-4-methoxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno(2,3-b) pyridinium

NMR Spectrum: DMSO 400 MHz 3.54 (d) approx. 3.68 (d): ═C--CH₂ S; 5.18(m): the H₆ 's; 5.76 (m): 5.96 (m): H₇ ; 5.72 (s): 5.74 (s): theφ--OMe's; 5.67 (m): CH₂ --CH═; 5.83 (s): 5.87 (s): C--CH--φ; approx. 6.8(s) resolved: the H thiazoles; 6.42 (m): 6.73 (m): H₅, H₆ ; 6.30 (m):7.15 (d) resolved: ═C--CH═CH--CH (ΔE); 7.88 (d): H₃ '; 8.29 (d ): H₂ ';8.15 (m): H₅ '; 9.08 (d): H₄ '; 9.22 (d): H₆ '; 9.44 (d): 9.53 (d):═C--NH--CH; 7.44 (m): 8.60 to 8.90: mobile H_(s).

EXAMPLE 51 Internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,3-dihydroxy-4-methoxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo(1,2-a) pyridinium

NMR Spectrum: DMSO 300 MHz 7.35 (m): 8.69 (m): 8.82 (m): mobile H's;3.52 (m) approx. 3.70 (m): CH₂ S; 3.74 (s): 3.75 (s): CH₃ O--φ; 5.15 (d,resolved): H₆ ; 5.74 (dd, d after exchange): 5.81 (dd, d aftr exchange):H₇ ; 5.29 (m): CH₂ --N⁺ : 5.83 (s): 5.86 (s): O--CH--φ; 6.25 (m): 6.90(d, resolved): CH═CH--CH₂ ; 6.43 (d): H₆ '; 6.72 to 6.80 (m): H₅ ' andH₅ thiazole; 7.58 (t): H_(5") ; 8.06 (t): H₆ "; 8.21 (d): 8 96 (d): H₄"H₇ ", 8.29 (sl): H₃ "; 8.44 (sl): H₂ "; 9.44 (d): 9.54 (d): CO-NH--CH.

EXAMPLE 52 Internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,3,4,trihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazol(1,2-a)pyridinium

NMR Spectrum: DMSO 300 MHz 3.54(m): CH₂ S; 5.15 (d); H₆ ; 5.82 (m): H₇and O--CH--φ; 5.28 (m): ═CH--CH --N⁺ ; 6.26 (m): CH═; 6.5 to 7.4 (m):aromatic 6H; 7.58 (t): H₅ '; 8.06 (t): H₆ '; 8.20 (d): 8.96 (d): H₄ ',H₇ '; 8.29 (sl): 8.44 (sl): H₂ ', H₃ '; 9.41 (d): 9.53 (d): CO--NH--CH;8.68 (m): 9.27 (m): 7.36 (m): mobile H's.

EXAMPLE 53 Internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl)-imidazo (1,2-a) pyridinium

NMR Spectrum: DMSO 300 MHz approx. 3.70: CH₂ S; 5.09 (d): 5 14 (d): H₆ ;5.29 (m): CH₂ --N⁺ ; 5.58 (s): 5.59 (s): O--CH--o; 5.72 (m): H₇ ; 6.22(m): CH═CH--CH₂ ; 6.68 (m): H₆ '; 6.77 (s): 6.789 (s): H₅ thiazole; 6.85(d, J=16): ═C--CH═CH; 7.58 (t): 8.06 (t): H₅ 641 , H₆ "; 8.19 (d): 8.96(d): J₄ ", H₇ "; 8.28(m): 8.44 (sl): H₂ ", H₃ "; 7.32 (m): 9.5 to 9.9(m): mobile H's.

EXAMPLE 54 Internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-2,3-difluoro-4,5-dihydroxyrphenyl)-methoxy)-imino]-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)quinolinium

NMR Spectrum: DMSO 300 MHz 3.45 (m):L CH₂ S; 5.09 (d): 5.14 (d): H₆ ;5.72 (m): H₇ ; 5.58 (s): 5.59 (s): O--CHCO; 5.88 (m): CH--N⁺ ; 6.34 (m):CH═CH--CH₂ ; 6.94 (d, J=16): 6.97 (d, J=16 ): CH═CH--CH₂ ; 6.67 (m): H₆"; 6.76 (s): 6.77 (s): H₅ thiazole; 8.07 (m): 8.26 (m): 8.53 (m): 9.34(d): 9.57 (d): quinoline; 7.32 (m): 9.5 to 9.9 (m): mobile H's.

EXAMPLE 55 Internal salt of (6R-(3-(E)6α,7β(Z)))-1=(3-(7-(((2-amino-4-thiazoyl)(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-8-thia-1-azabicyclo[4,2,0]oct-2-3-yl)-2-propenyl)pyridinium

NMR Spectrum: DMSO 300 MHz 3.58 (m): CH₂ S; 5.18 (d,d): H₆ ; 5.79 (m):H₇ ; 5.41 (sl): CH₂ N⁺ ; 5.64 (s): 5.65 (s): O--CH--C═; 6.30 (m):CH═CH--CH₂ ; 7.02 (dd, J=16): CH═CH--CH₂ ; 6.70 (dd): H₆ '; 6.78 (s):6.80. (s): H₅ thiazole; 8.18 (m): H₃ ", H₅ "; 8.63 (m): H₄ "; 9.05 (d):H₂ ", H₆ "; 9.35 (d): 9.62 (d): CO--NHCH; 7.33 (m): 9.80 (m): mobile H.

EXAMPLE 56 Internal salt of (6R-3-(E)6α,7β(Z)))-1-(3-(7-(((2amino-4-thiazolyl)(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2 -en-3-yl)-2-propenyl)-6,7-dihydro-5H-pyrindinium

NMR Spectrum: DMSO (300 MHz) 2.24 (m): CH₂ in position 6'; 3.14 (m)-3.37(m): CH₂ in position 5' and 7'; 3.56 (m): CH₂ S; 5.15 (d)-5.18 (d): H6;5.79 (m): H₇ ; 5.33 (d ): ═CH--CH₂ --N⁺ ; 5.63 (s)-5.65 (s): O--CH--φ;6.23 (m): CH═CH--CH₂ ; 6.85 (d)-6.88 (d, J=16): CH═CH--CH₂ ; 6.71 (dd,J=10.5 and 6): H₆ "; 6.78 (s)-6.81 (s): H₅ thiazole; 7.91 (m): H₃ ';8.43 (d, J=8): H₄ '; 8.76 (d, J=6): H₂ '; 9.54 (d)-9.63 (d): CH--NH--CO;7.35 (m)-9.85 (m): mobile H's.

EXAMPLE 57 Internal salt of (6R -(3(E) 6α,7β(Z)))-1(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,5-difluoro-3-4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl) quinolinium

NMR Spectrum: DMSO (300 MHz) 3.4 to 3.7 (m): CH₂ S; 5.15 (dd): H₆ ; 5.79(m): H₇ ; 5.62 (s)-5.64(s): --O--CH-- ; 5.89 (m):═CH--CH₂ --N+; 6.37(m): CH═CH--CH₂ ; 6.97 (dd, J=15.5): CH═CH--CH₂ ; 6.76 (s)-6.80 (s): H₅thiazole; 6.70 (dd, J=11 and 6): H₆ "; 8.07 (m)-8.27 (m)-8.53 (m)-9.34(d): quinoline; 9.58 (d): H₂ ; 9.53 (d)-9.62 (d): CO--NH--CH; 7.30(m)-9.83 (m): mobile H.

EXAMPLE 58 Internal salt of (6R-(3-(E) 6α,7β(Z)))-3-(3-(7-amino-4-thiazolyl)(carboxy-2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)thiazolium

NMR Spectrum: DMSO C300 MHz). 3.50 to 3.75 (m): CH₂ S; 5.16 to 5.19 (d):H₆ ; 5.81 (m): H₇ ; 5.33 (m): ═CH--CH₂ --N⁺ ; 5.63 (s)-5.65 (s):O--CH--φ; 6.26 (m) CH═CH--CH₂ ; 6.71 (dd, J=6 and 11): H₆ "; 6.78(s)-6.81 (s): H₅ thiazole; 8.37 (m)-8.51 (m): H₄ ', H₅ '; 10.20 (sl): H₂'; 7.30 (m): 9.5 to 9.9 (m)-13.25 (m)-13.75 (m): mobile H's.

EXAMPLE 59 Internal salt of (6R -(3-(E)6α,7β(Z)))-2-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)isoquinolinium

NMR Spectrum: DMSO (300 MHz) 3.50 to 3.75 (m): CH₂ S; 5.18 (dd): H₆ ;5.80 (m) H₇ ; 5.53 (d): ═CH--CH₂ N⁺ ; 5.63 (s)-5.65 (s): O--CH--φ; 6.37(m): CH═CH--CH₂ ; 7.09 (dd, J=15.5): CH═CH--CH₂ ; 6.71 (dd, J-11 and 6):H₆ "; 6.78 -(s) 6.80 (s): H₅ thiazole; 8.09 (t)-8.28 (t): H₆ ', H₇ ';8.37 (d)-8.53 (d): H₅ ', H₈ '; 8.61 (d)-8.74 (d): H₃ ', H₄ ; 10.06 (s)H₁ '; 7.35 (m)-9.84 (m): mobile H's; 9.56 (d)-9.65 (d): CH--NH--CO.

EXAMPLE 60 Internal salt of (6R-(3-(E) 6α,7β-(Z))) 1-(3-(7-(((2-amino4-thiazolyl) (carboxy (2,5-difluoro 3,4-dihydroxy phenyl) methoxy)imino) acetamido) 2-carboxy 8-oxo5-thia 1-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) 4-(methylthio)pyridinium

NMR Spectrum: (DMSO) 300 MHz 2,71 (s): φSMe; 3,54 (d), 3,66 (d); CH--S;5,17 (m): les H₆ ; 5,22 (s,1): ═CH--CH₂ --N⁺ ; 5.63 (s) resolved:OCH--φ; 5,79 (m): les H₇ ; 6,26 (m) CH═CH--CH₂ ΔE; 6,98 (d,J=l⁶)resolved: CH═CH--CH₂ ; 6,71 (dd, J=6 et 11): H difluorophenyl; 6,78 (s)resolved: H₅ thiazole; 7,30 (s,1): NH₂ ; 7,95 (d), 8,70 (d):methylthiopyridinium; 9,62-9,67 (d), 9.85 : H mobile; 19,49.

EXAMPLE 61 Internal salt of (6R-(3-(E) 6α,7β-(Z)))4-(3-(7-(((2-amino4-thiazolyl) (carboxy (2,5-difluoro 3,4-dihydroxy phenyl) methoxy)imino) acetamido) 2-carboxy 8-oxo 1-azabicyclo 5-thia 1-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl) 2-amino thiazolo (5,4-b)pyridinium

NMR Spectrum: (DMSO) 300 MHz 3,60: CH₂ S; 5,19 (d) resolved: H₆ ; 5,81(d): H₇ ; 5,47 (d): ═CH--CH--₂ --N⁺, 5,63 (s) : O--CH--φ; 6,21 (m)CH═CH--CH₂, 7,08 (d) resolved J=16: CH═CH--CH₂, 6,78 (s): H₅ thiazole;6,70 (dd, J=6 et 11): H₆ "; 7,83 (m) : H₅ '; 8.29 CH--NH--CO; 8,73 (s),9,84 (m), 7,33 (m): H mobile.

EXAMPLE 62 Internal salt of (6R-(3-(E) 6α,7β-(Z)))7-(3-(7-(((2-amino4-thiazolyl) (carboxy (2,5-difluoro 3,4-dihydroxy phenyl) methoxy)imino) acetamido) 2-carboxy 8-oxo 5-thia1-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl)thieno (2,3,-b)-pyridinium

NMR Spectrum: (DMSO) 3,4 to 3,8: CH₂ S; 5,18 (d, resolved): H₆ ; 5,81(dd, resolved-): H₇ ; 5,66 (m) 3H ═CH--CH₂ --N⁺ et O--CH-- ; 6,30 (m)CH═CH--CH₂, 7,14 (d, resolved, J=16: CH═CH--CH₂ ; 6,70 (dd, J=6 et 11):H₆ "; 6,77 (s), 6,81 (s): H₅ thiazole; 7,89 (d, J=6): H₃ '; 8,28 (d,J=6): H₂ '; 8,16 (m): H₅ '; 9,09 (d, J=8): H₄ '; 9.23 (d, J=6): H₆ ';9,35 (d), 9,65 (d): CO--NH--CH; 7,32 (m), 9,83 (m): H mobile.

EXAMPLE 63 Internal salt of (6R-(3-(E) 6α, 7β-(Z)))7-(3-(7-(((2-amino4-thiazolyl) (carboxy (3,4-dihydroxy 2,5-difluorophenyl) methoxy) imino)acetamido) 2-carboxy 8-oxo 5-thia 1-azabicyclo [4,2,0]oct-2-en-3-yl)2-propenyl) imidazo (2,1-b)-thiazolium EXAMPLE 64 Internal salt of(6R-(3-(E) 6α,7β-(Z)))3-(3-(7-(((2-amino 4-thiazolyl) (carboxy(3,4-dihydroxy 2,5-difluorophenyl) methoxy) imino) acetamido) 2-carboxy8-oxo 5-thia 1-azabicyclo [4,2,0]oct-2 -en-3-yl) 2-propenyl) 1-methyl1H-benzimidazolim EXAMPLE 65 Internal salt of (6R-(3-(E) 6α,7β-(Z)))7-(3-(7-(((2-amino 4-thiazolyl) (carboxy(3,4-dihydroxy2,5-difluorophenyl) methoxy) imino) acetamido) 2-carboxy8-oxo 5-thia 1-azabicyclo[4,2,0]oct-2-en-3-yl) 2-propenyl)4-methylthieno (2,3-b)-pyridinium

In addition to the compounds described above, the following productsconstitute compounds which can be obtained by the methods of theinvention.

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EXAMPLE 66

Internal salt of [6R-(3-(E)6α,7β-(Z))]-1-(3-(7-[((2-amino-4-thiazolyl)-((carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo(1,2-a)pyridinium

Stage A:1-[3-[7β-[[[[[1-[2,3-difluoro-4,5bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-imidazo(1,2-a)pyridiniumiodide

Using the procedure of Stage H of Example 1, 600 mg of the iodatedderivative obtained below and 0.215 ml of imidazo(1,2-a) pyridine werereacted to obtain after chromatograph on silica (eluant methylenechloride--methanol (95-5)), 534 mg of the desired product.

NMR spectrum: CDCl₃ 300 MHz. 3.17 (s), 3.25 (s), 3.35 (s), 3.36 (s): theOMe's; 3.78, 3.79: the Φ--OMe's; 3.30 to 4.00:--O--CH₂ --CH₂ --O and═C--CH₂ S; 4.93 (m): H₆ ; 5.76 to 5.89: H₇ ; 4.98 to 5.35: O--CH₂ --Oand COOCH₂ --Φ; 6.28 (m): ═CH--CH₂ ΔE; 6.34 (s), 6.36 (s): C--C--Φ; 6.76(s), 6.77 (s): H₅ thiazole; 6.85 to 7.35: the phenyls, COOCH--Φ₂ ; 7.87(m) 1H, 8.04 (t) 1H, 8.39 (d) resolved 1H, 8.61 (d) resolved 1H, 9.09(t) 1H: imidazopyridine; 7.73, 8.19: ##STR262##

Stage B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-((2-amino-4-thiazolyl)-((carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo(1,2-a)pyridinium

Using the procedure of Stage I of Example 1 191 mg of the product ofStage A and 2 ml of trifluoroacetic acid with 10% anisole were reactedto obtain 66 mg of the expected product.

NMR spectrum: DMSO (300 MHz) ˜3.70: CH₂ S; 5.09 (d)-5.14 (d): H₆ ; 5.29(m): CH₂ --N⊕; 5.58 (s)-5.59 (s): O--CHΦ; 5.72 (m): H₇ ; 6.22 (m):CH═CH--CH₂ ; 6.68 (m): H₆ '; 6.77 (s)-6.78 (s): H₅ thiazole; 6.85 (d,J=16): ═C--CH═CH--; 7.58 (t)-8.06 (t): H₅ ", H₆ "; 8.19 (d)-8.96 (d): H₄", H₇ "; 8.28 (m)-8.44 (sl): H₂ ", H₃ "; 7.32 (m), 9.5 to 9.9 (m):mobile H's.

Preparation of 4-methoxybenzyl7β-[[[[[1-[2,3-difluoro-4,5bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]thiazol-4-yl]-acetamido]-3-[(Z)3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylateused at the start of Example 53.

Stage A: 2,3-difluoro 6-methoxy phenol

Using the procedure of Example 39, 125 g of 3,4-difluoroanisole(commercial) and 500 ml of a 1.6 M solution of N-butyllithium in hexanewere reacted at -72° C., and then 92.4 ml of trimethylborate, 500 ml ofhydrochloric acid and 120 g of intermediate compound were reacted andthe product was reacted with 440 ml of 30% hydrogen peroxide to obtain82.4 g of the expected product melting at 46.6° C.

Stage B: 2,3-difluoro-4-hydroxy-5-methoxy-benzaldehyde

47 g of the product of Stage A in solution in 100 ml of ethanol wereadded dropwise over approximately 15 minutes to a solution of 62 g ofdimethylamine (in aqueous solution at 40%), 375 ml of formalin and 290ml of ethanol. The reaction mixture was refluxed for 3 hours and thesolvent was eliminated. The residue was taken up in 400 ml of ether andfiltered to obtain 51.3 g of intermediate methylated dimethylamino whichwas dissolved in 500 ml of a methylene chloride--methanol mixture(50-50). Then, 250 ml of methyl iodide were added and the mixture wasstirred for 16 hours at ambient temperature, followed by filtering toobtain 88 g of the intermediate quaternary amine melting at 140° C. Thisintermediate product was heated for 3 hours at reflux in a mixture of250 ml of acetic acid, 250 ml of water and 150 g of hexamethylenetetramine. 63 ml of concentrated hydrochloric acid were added, followedby stirring for 20 minutes at reflux, cooling the reaction medium andextracting with ethyl acetate to obtain 33.2 g of the expected aldehyde.

Stage C: 2,3-difluoro-4,5bis[(2-methoxyethoxy)-methoxy]-benzaldehyde

Using the procedure of Stage C of Preparation 3, 36.6 g of the productof Stage B, 214 ml of diisopropylethylamine and 92 ml ofchloro(2-methoxy ethoxy) methane were reacted to obtain 65.4 g of theexpected product with a Rf=0.4 (methylene chloride--acetone 9-1).

Stage D:[2,3-difluoro-4,5-bis[2-methoxyethoxy)-methoxy]styryl-carboxylate

Using the procedure of Stage B of Example 40, 65.4 g of the aldehyde ofStage C were reacted to obtain 103 g of crude product which waschromatographed on silica (eluant: methylene chloride-ethyl acetate 9-1)to obtain 44.3 g of the expected product.

Stage E: [2,3-difluoro-4,5-bis[(2-methoxyethoxy)-methoxyl]styrol

Using the procedure of Stage C of Example 40, 44.3 g of the ester ofStage D and 230 ml of a molar solution of dissobutyl-aluminum hydride inhexane were reacted to obtain 32 g of the expected product.

Stage F: [2,3-difluoro 4,5-bis[(2-methoxyethoxy) methoxy](1,2-epoxy)styrol

Using the procedure of Stage D of Example 40, 32 g of the product ofStage E were reacted to obtain 33.5 g of the expected product with aRf=0.14 (CH₂ Cl₂ -AcOEt 8-2).

Stage G: diphenylmethyl[[2,3-difluoro-4,5-bis[(2-methoxy-ethoxy)-methoxy]-phenyl]-chloro-acetate

Using the procedure of Stage E of Example 40, 33.5 g of the epoxide ofStage F were reacted to obtain 15.6 g of the intermediate diol. 32.78 gof sodium periodate and 424 mg of hydrated ruthenium chloride werereacted with 16.6 g of chlorodiol prepared in an identical manner toobtain 15.6 g of the intermediate acid which was reacted with 7.5 g dediphenyldiazomethane to obtain 21 g of the expected product with Rf=0.4(CHCl₂ --AcOEt 8-2).

Stage H: diphenylmethylaminoxy[[2,3-difluoro-4,5-bis[(2-methoxyethoxy)-methoxy]-phenyl]-acetate

Using the procedure of Stage F of Example 40, 20 g of the chlorinatedderivative of Stage G were reacted to obtain 13 g of the expectedproduct with a Rf=0.2 (AcOEt -CH₂ Cl₂ 1-3).

Stage I: [[1-[2,3-difluoro-4,5bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino][2-[(triphenylmethyl)-amino]-thiazol-4-yl]-aceticacid

Using the procedure of Stage E of Example 1, 12 g of the product ofStage H and 9.45 mg of oxo [2-[(triphenylmethyl)amino]thiazol-4-yl]acetic acid (described in Belgian Application No.864828) were reacted to obtain the product which was not isolated andtreated as is in the following stage.

Stage J:4-methoxy-benzyl7β-[[[[1-[2.3-difluoro-4,5bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]oxy]-imino]-[2-(triphenylmethyl)-amino]thiazol4-yl]acetamido]-3-(Z)3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en2-carboxylate

Using the procedure of Stage F of Example 1, the crude product of StageI and 12.89 g of 4-methoxy-benzyl 7β-amino 3-[(Z)3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylatehydrochloride (EP 0,33,154) were reacted to obtain after chromatographyon silica, (eluant: methylene chloride-ethyl acetate (9-1)). 14 g of thedesired product with a Rf=0.23 (CH₂ Cl₂ -AcOEt 9-1).

Stage K: 4-methoxy-benzyl7β-[[[[1-[2,3-difluoro-4,5bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)ethyl]oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]acetamido]-3[(Z)3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate

Using the procedure of Stage G of Example 1, 6 g of the product of StepJ were reacted to obtain after chromatography on silica (eluant:methylene chloride--ethyl acetate (9-1)) 5 g of the desired product witha Rf=0.27 (CHCl₂ -AcOEt 9-1).

EXAMPLE 67 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-quinolinium

Using the procedure of Stages A and B of Example 66, 750 mg of theiodated derivative prepared above and the appropriate amine were reactedto obtain 420 mg of the intermediate quaternary salt which was reactedwith 4 ml of trifluoroacetic acid with 10% anisole to obtain 220 mg ofthe expected product.

NMR spectrum: DMSO (300 MHz) 3.45 (m): CH₂ S; 5.09 (d)-5.14 (d): H₆ ;5.72 (m): H₇ ; 5.58 (s)-5.59 (s): O--CH--CO; 5.88 (m): CH₂ --N.sup.⊕ ;6.34 (m): CH═CH--CH₂ ; 6.94 (d, J=16)-6.97 (d, J=16): CH═CH--CH₂ ; 6.67(m): H₆ "; 6.76 (s)-6.77 (s): H₅ thiazole; 8.07 (m)-8.26 (m)-8.53(m)-9.34 (d)-9.57 (d): quinoline; 7.32 (m)-9.5 to 9.9 (m): mobile H's.

EXAMPLE 68 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-pyridinium

Stage A:1-[3-[7β-[[[[[1-[2,5-difluoro-3,4bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy)-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]pyridiniumiodide

713 mg of 4-methoxybenzyl7β-[[[[[1-[2,5-difluoro-2,4bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)amino]-thiazol-4-yl]-acetamido]-3-[(Z) 3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo [4,2,0]oct-2-en-2-carboxylate of Stage G ofExample 39 were mixed with 205 mg of pyridine and 10 ml of methylenechloride. The solvent was evaporated and the mixture was stirred for 1hour. After taking up in ether and stirring for 1 hour, the crystallizedproduct was separated out, washed with ether and dried for 16 hoursunder reduced pressure to obtain after chromatography on silica (eluant:methylene chloride--methanol (95-5)), 106 mg of the desired product withRf=0.2.

NMR spectrum: CDCl₃ 400 MHz 3.33-3.34 (s): C--O--CH₃ ; 3.54-3.92 (m):central CH₂ 's; 3.30-3.80: CH₂ S; 3.79 (s): Ar--O--CH₃ ; 4.97 (dd): H₆cephalo; 5.80-5.91 (d) after exchange: H₇ cephalo; 6.28 (m)-6.47 (dt):═CH--CH₂ N.sup.⊕ ; 6.32 (s)-6.38 (s): ##STR263## 7.94-8.24 (d):CO--NH--CH; 8.02 to 9.23: pyridine; 6.75-7.40 (m): aromatic, CH═CH--CH₂,CO₂ --CH--Φ₂ ; 5.55-5.75: CH₂ --N.sup.⊕ ; 5.24 (m): OCH₂ O, ##STR264##

Stage B:

Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-pyridinium

98 mg of the product of Stage A in 3 ml of trifluoroacetic acid with 10%anisole were stirred for 2 hours at ambient temperature. The solutionwas poured into 75 ml of ether and stirred for 1 hour. The crystallizedproduct was separated out, washed with ether and dried for 16 hoursunder reduced pressure to obtain 46 mg of the expected product.

NMR spectrum: DMSO (400 MHz) 3.58 (m): CH₂ S; 5.18 (d,d): H₆ ; 5.79 (m):H₇ ; 5.41 (sl): CH₂ N.sup.⊕ ; 5.64 (s)-5.65 (s): O--CH--C═; 6.30 (m):CH═CH--CH₂ ; 7.02 (dd, J=16): CH═CH--CH₂ ; 6.70 (dd): H₆ '; 6.78(s)-6.80 (s): H₅ thiazole; 8.18 (m) H₃ ", H₅ "; 8.63 (m): H₄ ", 9.05(d): H₂ ", H₆ "; 9.35 (d)-9.62 (d): CO--NHCH; 7.33 (m)-9.80 (m): mobileH.

EXAMPLE 69 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-6,7-dihydro-5H-pyrindinium

Stage A:1-[3-[7β-[[[[[1-[2,5-difluoro-3,4bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]oxy]imino]-[2-(triphenylmethyl]-amino]-thiazol-4-yl]-acetamido]-2-[(4methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-6,7-dihydro-5H-pyrindinium iodide

Using the procedure of Stage A of Example 68, 2.008 g of the iodatedderivative and 843 mg of 2,3-cyclopentenopyridine were reacted to obtain1.7 g of the expected product with a Rf=0.2 (methylenechloride--methanol 95-5).

Stage B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)imido)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-6,7-dihydro-5H-pyrindinium

Using the procedure of Stage B of Example 68, 656 mg of the product ofStage A and 7 ml of trifluoroacetic acid with 10% anisole were reactedto obtain the expected product.

NMR spectrum: DMSO (300 MHz) 2.24 (m): CH₂ in position 6'; 3.14 (m)-3.37(m): CH₂ in position 5' and 7"; 3.56 (m): CH₂ S; 5.15 (d)-5.18 (d): H₆ ;5.79 (m): H₇ ; 5.33 (d): ═CH--CH₂ --N.sup.⊕ ; 5.63 (s)-5.65 (s):O--CH--Φ; 6.23 (m): CH═C--CH₂ ; 6.85 (d)-6.88 (d, J=16): CH═CH--CH₂ ;6.71 (dd, J=10.5 and 6): H₆ "; 6.78 (s)-6.81 (s): H₅ thiazole; 7.91 (m):H₃ '; 8.43 (d, J=8): H₄ '; 8.76 (d, J=6): H₂ '; 9.54 (d)-9,63 (d):CH--NH--CO; 7.35 (m)-9.85 (m): mobile H's

EXAMPLE 70 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-quinolinium

Stage A:1-[3-[7β-[[[[[1-[2,5-difluoro-3,4bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium iodide

Using the procedure of Stage A of Example 68, 940 mg of the iodatedderivative and 430 mg of quinoline were reacted to obtain 821 mg of theexpected product with a Rf=0.2 (methylene chloride--methanol 95-5).

NMR spectrum: CDCl₃ 300 MHz 3.32-3.34-3.35 (s): C--O--CH₃ ; 3.54-3.91(m): central CH₂ 's and CH₂ S; 3.79 (s): Ar--O--CH_(3;) 4.93 (dd): H₆cephalo; 5.80-5.87 (m): H₇ cephalo; 6.35 (m)-6.56 (m): CH--CH--CH₂ ;6.31 (s)-6.37 (s): ##STR265## 7.93 to 8.96: quinoline; 6.85-7.40 (m):aromatic, CH═CH--CH₂, CO₂ --CH--Φ₂ ; 5.15-5.30 OCH₂ O, ##STR266##5.95-6.05: CH₂ --N⁺ ; 6.85-7.40: H₅ thiazole.

Stage B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-quinolinium

Using the procedure of Stage B of Example 68, 802 mg of the product ofStage A and 10 ml of trifluoroacetic acid with 10% anisole were reactedto obtain 437 mg of the expected product.

NMR spectrum: DMSO (300 MHz) 3.4 to 3.7 (m): CH₂ S; 5.15 (dd): H₆ ; 5.79(m): H₇ ; 5.62 (s)-5.64 (s): --O--CH--Φ; 5.89 (m): ═CH--CH₂ --N.sup.⊕6.37 (m): CH═CH--CH₂ ; 6.97 (dd, J=15.5): CH═CH--CH₂ ; 6.76 (s)-6.80(s): H₅ thiazole; 6.70 (dd, J=11 and 6): H₆ "; 8.07 (m)-8.27 (m)-8.53(m)-9.34 (d): quinoline; 9.58 (d): H₂ ; 9.53 (d)-9.62 (d): CO--NH--CH;7.30 (m)-9.83 (m): mobile H.

EXAMPLE 71 Internal salt of (6R-(3-(E)6α,7β-(Z)))-3-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thiazolium

Stage A:3-[3-[7β-[[[[[1-[2,5-difluoro-3,4bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(ciphenyl-methoxy)-ethyl]-oxy]imino]-[2-(triphenylmethyl)-amino]-thiazol-yl]-acetamido]-2-[4-methoxhybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-thiazoliumiodide

Using the procedure of Stage A of Example 68, 856 mg of the iodatedderivative and 285 mg of thiazole were reacted to obtain 516 mg of theexpected product with a Rf=0.2 (methylene chloride --methanol 95-5).

NMR spectrum: CDCl₃ 300 MHz 3.32-3.36 (s): the C--O--CH₃ 's; 3.54-3.92(m): the central CH₂ 's and CH₂ S; 3.78 (s) : Ar--O--CH₃ ; 4.97 (m) : H₆cephalo; 5.25 (m): OCH₂ O, CO₂ CH₂ Ar; 5.39 (m)-5.57 (m): CH₂ N.sup.⊕ ;5.74-5.90 (m) : H₇ cephalo, 6.10-6.32 (m): ═CH--CH₂ N.sup.⊕ ; 6.32(s)-6.38 (s): ArCHO; 6.87 (s)-6.90 (s): CO₂ --CH--Φ₂ ; 6.76-6.78 (s): H₅thiazole; 6.95 to 7.36: aromatic H's; 7.91: NH--CH--; 8.21-10.90-10.94:H' of the thiazole.

Stage B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-3-(3-(7-(((2-amino-4-thiazolyl)-((carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thiazolium

Using the procedure of Stage B of Example 68, 504 mg of the product ofStage A and 8 ml of trifluoroacetic acid with 10% anisole were reactedto obtain 238 mg of the expected product.

NMR spectrum: DMSO (300 MHz) 3.50 to 3.75 (m): CH₂ S; 5.76 to 5.79 (d):H₆ ; 5.81 (m): H₇ ; 5.33 (m): ═CH--CH₂ --N.sup.⊕ ; 5.63 (s)-5.65 (s):O--CH--Φ; 6.26 (m): CH═CH--CH₂ ; 6.96 (dd, J=16): CH═CH--CH₂ ; 6.71 (dd,J=6 and 11): H₆ "; 6.78 (s)-6.87 (s): H₅ thiazole; 8.37 (m)-8.51 (m): H₄', H₅ '; 70.20 (sl): H₂ '; 7.30 (m): 9.5 to 9.9 (m)-73.25 (m)-3.75 (m):mobile H's.

EXAMPLE 72 Internal salt of (6R-(3-(E)6α,7β-(Z)))-2-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-isoquinolinium

Stage A:2-[3-[7β-[[[[[1-[2,5-difluoro-3,4bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetyl]-amino]-2[[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-isoquinoliniumiodide

Using the procedure of Stage A of Example 68, 856 mg of the iodatedderivative and 369 mg of isoquinoline were reacted to obtain the 827 mgof the expected product with a Rf=0.2 (methylene chloride--methanol95-5)

NMR spectrum: DMSO 300 MHz 3.31 (s)-3.32 (s)-3.33 (s)-3.39 (s): C--CH₃ ;3.79 (s): Ar--O--CH₃ ; 3.44-4.00: OCH₂ CH₂ O and CH₂ S; 5.24 (m): OCH₂ Oand CO₂ --CH₂ --Ar; 4.95 (dd): H₆ cephalo; 5.63 (m): H₇ cephalo; 5.88(m): CH₂ --N.sup.⊕ ; 6.32-(s)-6.38 (s): ##STR267## 6.36 (m)-6.56 (m):CH--CH₂ N.sup.⊕ ; 6.75 (s)-6.77 (s) : H₅ thiazole; 6.88-7.40:CH═CH--CH₂, CO₂ CH--φ₂ and aromatic H's; 7.90-8.70 and 10.93 (s) -10.98(s): pyridine.

Stage B: Internal salt of [6R-(3-(E)6α,7β-(Z)))-2-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2.0]oct-2-en-3-yl)-2-propenyl)-isoquinolinium

Using the procedure of Stage B of Example 68, 807 mg of the product ofStage A and 10 ml of trifluoroacetic acid with 10% anisole were reactedto obtain 402 mg of the expected product.

NMR spectrum: DMSO (300 MHz) 3.53 to 3.75 (m): CH₂ S; 5.18 (dd): H₆ ;5.80 (m): H₇ ; 5.53 (d): ═CH--CH₂ --N.sup.⊕ ; 5.63 (s)-5.65 (s):--O--CH--Φ; 6.37 (m): CH═CH--CH₂ ; 7.09 (dd, J=5.5): CH═CH--CH₂ ; 6.71(dd, J=11 and 6): H₆ "; 6.78 (s)-6.80 (s): H₅ thiazole; 8.09 (t)-8.28(t): H₆ ', H₇ '; 8.37 (d)-8.53 (d): H₅ ', H₈ '; 8.61 (d)-8.74 (d): H₃ ',H₄ '; 10.06 (s): H₁ '; 7.35 (m)-9.84 (m): mobile H's; 9.56 (d)-9.65 (d):CH--NH--CO.

EXAMPLE 73 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-4-(methylthio)pyridinium

Stage A:1-[3-[7β-[[[[[1-[2,5-difluoro-3,4bis-[(2-methoxyethoxy)-methoxy]phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-4-(methylthio)-pyridinium iodide

Using the procedure of Stage A of Example 68, 855 mg of the iodatedderivative and 371 mg of 4-methylthiopyridine were reacted to obtain 807mg of the expected product with a Rf=0.2 (methylene chloride--methanol95-5)

NMR spectrum: CDCl₃ 400 MHz 2.60 (s)-2.62 (s): CH₂ S; 3.33-3.34 (s): theC--O--CH₃ 's; 3.45-3.60-3.92 (m): the central CH₂ 's; 3.79 (s):Ar--O--CH₃ ; 4.96 (m): H₆ cephalo; 5.24 (m): OCH₂ O, CO₂ CH₂ Ar; 5.36(m)-5.55 (m): CH₂ N.sup.⊕ ; 5.78-5.91: H₇ cephalo, 6.17-6.50 (m):CH--CH₂ (ΔE) 6.33 (s)-6.38 (s): ##STR268## 6.75 (s)-6.77 (s): H₅thiazole; 6.76: H₆ fluorophenyl; 6.90-7.40: aromatic H; CH═CH--CH₂ ;7.63 (t)-8.89 (dd): pyridine; 7.88 (d)-8.82 (d): CONHCH.

Stage B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-4-(methylthio)-pyridinium

Using the procedure of Stage B of Example 68, 790 mg of the product ofStage A and 10 ml of trifluoroacetic acid with 10% anisole were reactedto obtain 408 mg of the expected product.

NMR spectrum: (DMSO) 300 MHz 2.71 (s): ΦSMe; 3.54 (d), 3.66 (d): CH-S;5.77 (m): the H₆ 's 5.22 (s,1): ═CH--CH₂ --N⁺ ; 5.63 (s) resolved:OCH--φ; 5.79 (m): the H₇ 's; 6.26 (m) CH═C--CH₂ ΔE, 6.98 (d, J=16)resolved: CH═CH--CH₂ ; 6.71 (dd, J=6 and 11 ): H₆ "; 6.78 (s) resolved:H₅ thiazole; 7.30 (sl): NH₂ ; 7.95 (d), 8.70 (d): N --S; 9.62-9.67 (d),9.85: the mobile H's; 19.49.

EXAMPLE 74 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-1-azabicyclo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-2-amino-thiazolo(5,4-b)-pyridinium

Stage A:1-[3-[7β-[[[[[1-[2,5-difluoro-3,4bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino-[2-(triphenylmethyl]-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-2-amino-thiazolo(5,4-b)pyridinium iodide

Using the procedure of Stage A of Example 68, 579 mg of the iodatedderivative and 417 mg of 2-triphenyl-methylamino-thiazolo (5,4-b)pyridine in 4 ml of methylene chloride in the presence of 0.2 ml ofethanol were reacted and the reaction mixture was stirred for 30 hoursat 25° C. to obtain 328 mg of the expected product with a Rf=0.25(methylene chloride--methanol 90-10)

NMR spectrum: CDCl₃ 300 MHz 3.32-3.33-3.34 (s): COCH₃ ; 3.2 to 3.5: CH₂S; 3.54 (m)-3.92 (m): the central CH₂ 's; 3.78 (s)-3.79 (s): Ar--O--CH₃; 5.01 (d, resolved): H₆ ; 5.88 (dd)-6.03 (dd): H₇ ; 5.24 (m): CH₂--N.sup.⊕ and O--CH₂ --O; 6.05 (m): CH═CH--CH₂ ; 6.33 (s)-6.39 (s):##STR269## 6.75-7.45; aromatic H's, CH═CH--CH₂, H₅ thiazole, CO₂--CH--Φ₂ ; 7.45 (d)-8.49 (d): CONHCH; 7.75 to 8.63: 2-amino thiazolo(5,4-b) pyridine.

Stage B: Internal salt of(6R-(3-(E)6α,7β-(Z)))-4-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-1-azabicyclo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-2-amino-thiazolo(5.4-b)-pyridinium

Using the procedure of Stage B of Example 68, 314 mg of the product ofStage A and 5 ml of trifluoroacetic acid with 10% anisole were reactedto obtain 126 mg of the expected product.

NMR spectrum: (DMSO) 300 MHz ˜3.60: CH₂ ; 5.19 (d) resolved: H₆ ; 5.81(d): H7; 5.47 (d): ═CH--CH₂ --N⁺ ; 5.63 (s), 5.65 (s): O--CH--Φ; 6.21(m): CH═CH--CH₂ ; 7.08 (d) resolved J=16: CH═CH--CH₂ ; 6.78 (s): H₅thiazole; 6.70 (dd, J=6 and 11): H₆ ; 7.83 (m): H₅ '; 8.29 (d, J=8): H₄'; 8.64 (d, J=6): H₆ '; 9.55 (d), 9.64 (d): CH--NH--CO; 8.73 (s), 9.84(m), 7.33 (m): mobile H.

EXAMPLE 75 Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno(2,3-b) pyridinium

Stage A:7-[3-[7β-[[[[[1-[2,5-difluoro-3,4bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-thieno(2,3-b) pyridinium iodide

Using the procedure of Stage A of Example 68, 894 mg of the iodatedderivative and 440 mg of thieno (2,3-b) pyridine were reacted to obtain754 mg of the expected product with a Rf=0.2 (methylenechloride--methanol 95-5)

NMR spectrum: CDCl₃ 300 MHz 3.32-3.33-3.34-3.35 (s): COCH₃ ; 3.4-3.6:CH₂ S; 3.79 (s)-3.81 (s resolved): Ar--O--CH₃ ; 3.54 (m)-3.92 (m): OCH₂CH₂ O; 4.98 (d, resolved)-5.02 (d, resolved): H₆ cephalosporin;5.17-5.35 (m) OCH₂ O, CO₂ CH₂ Ar; 5.82 (dd)-5.91 (dd): H₇ cephalosporin;5.24 (m): 6.32 (s)-6.38 (s): ##STR270## 5.6-6.55: (complex m): CH═;6.7-8.35 (complex m): aromatic H's, CO₂ --CH--Ph₂ ; 8.58 (m)-8.80 (m):aromatic H's; 9.72 (m): mobile H's.

Stage B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno(2,3-b) pyridinium

Using the procedure of Stage B of Example 68, 736 mg of the product ofStage A and 10 ml of trifluoroacetic acid with 10% anisole were reactedto obtain 322 mg of the expected product.

NMR spectrum: (DMSO) 3.4 to 3.8: CH₂ S; 5.18 (d, resolved): H₆ ; 5.81(dd, resolved): H₇ ; 5.66 (m) 3H═CH--CH₂ --N.sup.⊕ and O--CH--Φ; 6.30(m): CH═CH--CH₂ ; 7.14 (d, resolved, J=16): CH═CH--CH₂ ; 6.70 (dd. J=6and 11): H₆ "; 6.77 (s), 6.81 (s): H₅ thiazole; 7.89 (d, J=6): H₃ ';8.28 (d, J=6): H₂ '; 8.16 (m): H₅ '; 9.09 (d, J=8): H₄ '; 9.23 (d, J=6):H₆ '; 9.55 (d), 9.65 (d): CO--NH--CH; 7.32 (m), 9.83 (m): mobile H's.

EXAMPLE 76 Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(3,4-dihydroxy-2,5-difluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo(2,1-b)thiazolium

Stage A:7-[3-[7β-[[[[[1-[2,5-difluoro-3,4bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-imidazo(2,1-b) thiazolium iodide

Using the procedure of Stage A of Example 68, 553.5 mg of the iodatedderivative and 355 mg of imidazo (2,1-b) thiazole were reacted to obtainthe 494 mg of the expected product with Rf=0.2 (methylenechloride--methanol 95-5)

NMR spectrum: CDCl₃ 300 MHz 3.32-3.34: CH₃ O; 3:54 (m)-3.92 (m): OCH₂CH₂ O, CH₂ S; 3.79 (s): CH₃ OAr; 5.04 (m): H₆ cephatosporin; 5.81(m)-5.91 (m): H₇ cephalosporin; 6.00-6.35: ═CH--CH₂ ΔE; 6.33 (s)-6.38(s): ##STR271## 5.24 (m): ArCH₂ OCO; 6.76 (s)-6.7 (s): H₅ thiazole; 6.87(s)-6.90 (s): CO₂ --CH--Ph₂ ; 6.75-7.40: aromatic H (phenyl), CH═CH--CH₂ΔE, 1H of the imidazo (2,1q-b) thiazole; 8.02 (m)-8.31 (m)-8.37 (m): 3Hof the imidazothiazole; 7.96 (d)-8.24 (d): CONH--CH.

Stage B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(3,4-dihydroxy-2,5-difluoro-phenyl)-methoxyimino)-acetamido)-2-carboxy-8-oxo-5-this-1-azabicyclo[[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo(2,1-b)-thiazolium

Using the procedure of Stage B of Example 68, 477 mg of the product ofStage A and 5 ml of trifluoroacetic acid with 10% anisole were reactedto obtain 238 mg of the expected product.

NMR spectrum: DMSO 300 MHz 3.55-3.80: CH₂ S; 5.11-5.20 H₆ and CH--CH₂--N.sup.⊕ ; 5.81 (m): H₇ ; 6.80 (s, resolved): H₅ of the thiazole; 6.74(dd): H₆ ' of the fluorophenyl; 7.08 (d, resolved): CH═CH--CH₂ ; 7.31(sl): NH₂ ; 7.73-8.03-8.23-8.28: imidazo (2,1-b) thiazole; 9.56 (d)-9.65(d): CO--NH; 9.80-9.85: mobile H's.

EXAMPLE 77 Internal salt of (6R-(3-(E)6α,7β-(Z)))-3-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(3,4-dihydroxy-2,5-difluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-1-methyl-1H-benzimidazolium

Stage A:3-[3-[7β-[[[[[1-[2,5-difluoro-3,4bis-[(2-methoxyethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamino]-2[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]1-methyl-1H-benzimidazoliumiodide

Using the procedure of Stage A of Example 68, 513 mg of the iodatedderivative and 337 mg of 1-methyl benzimidazole were reacted to obtain472 mg of the expected product with a Rf=0.2 (methylenechloride--methanol 95-5)

NMR spectrum: CDCl₃ 300 MHz 3.33: CH₃ O--C; 3.54 (m)-3.75 (m): CH₂ S;OCH₂ CH₂ O; 3.91 (m): CH₃ OAr; 4.24 (s, resolved): CH₃ N<; 4.99 (d): H₆cephalosporin; 5.23 (m): OCH₂ O, CO₂ CH2Ar, 1H of CH₂ N.sup.⊕ ; 5.42(m): 1H of CH₂ N.sup.⊕ ; 5.89 (m): H₇ cephalosporin; 6.21-6.51: ═CH--CH₂; 6.32 (s)-6.37 (s): ##STR272## 6 76 (s, resolved): H₅ thiazole; 6.90(s): CO₂ CHPh₂ ; ˜6.91 (masked): fluorophenyl; 7.0-7.7: aromatic H's(except H₂ '): CH═CH--CH₂ ; 11.00 (s, resolved): H₂ ' of1-methyl-benzimidazole.

Stage B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-3-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(3,4-dihydroxy-2,5-difluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-1-methyl-1H-benzimidazolium

Using the procedure of Stage B of Example 68, 455 mg of the product ofStep A and 5 ml of trifluoroacetic acid with 10% anisole were reacted toobtain 213 mg of the expected product.

NMR spectrum: DMSO 300 MHz 3.5-3.7: CH₃ S; 4.09 (s): N--CH₃ ; 5.18 (d,resolved): H₆ ; 5.89 (m): H₇ ; 5.64 (s, resolved): OCHΦ; 6.79 (s,resolved): H₅ thiazole; 6.26 (m): CH═CH--CH₂ ; 6.70: H of thefluorophenyl; 7.09 (d, resolved): CH═CH--CH₂ ; 7.30 (sl): NH₂ ; 6.71(m)-8.02 (m): aromatic H's; 9.55 (d)-9.65 (d): NH--CO; 9.71: Hbenzimidazizole; 9.85: mobile H's.

EXAMPLE 78 Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(3,4-dihydroxy-2,5-difluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-4-methyl-thieno(2,3-b)-pyridinium

Stage A:7-[3-[7β-[[[[[1-[2,5-difluoro-3,4bis-[-2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-4-methyl-thieno(2,3-b) pyridinium iodide

Using the procedure of Stage A of Example 68,398 mg of the iodatedderivative and 405 mg of 4-methylthieno (2,3-b) pyridine were reacted toobtain 257 mg of the expected product with Rf=0.4 (methylenechloride--methanol 90-10)

NMR spectrum: CDCl₃ 300 MHz 2.93 (s, resolved): 4-methyl pyridine;3.33-3.34: CH₃ O--C; 3.55 (m)-3.93 (m): OCH₂ CH₂ O; 3.80 (s): CH₃ OAr;˜3.45-3.75: CH₂ ; 4.98 (d, resolved): H₆ cephalosporin; 5.24: OCH₂ O,CO₂ CH₂ Ar; 5.56-5.75-5.90: CH--CH₂ N.sup.⊕ ; 5.84 (m): H₇cephalosporin; 6.31 (s)-6.36 (s): ##STR273## 6.25-6.53: ═CH--CH₂ ΔE;6.75 (s)-6.77 (s): H₅ thiazole; 6.70-7.40: aromatic H's, CH═CH--CH₂ Eand H of the fluorophenyl; 7.66 (d, resolved)-7.84 (m)-8.24 (d)-9.62 (d,resolved): thieno (2,3-b) pyridine.

Stage B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(3,4-dihydroxy-2,5-difluoro-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-4-methyl-thieno(2,3-b)-pyridinium

Using the procedure of Stage B of Example 68,241 mg of the product ofStage A and 4 ml of trifluoroacetic acid with 10% anisole were reactedto obtain 132 mg of the expected product.

NMR spectrum: DMSO 300 MHz 2.91 (s): 4-methylpyridine; 5.17 (m): H₆cephalosporin; 5.62 (m): CH₂ N⁺ and Ar--CH--CO₂ ; 5.80 (m): H₇cephalosporin; 6.28 (m): CH═CH--CH₂ ; 6.70 (m): H of the fluorophenyl;6.77 (s)-6.80 (s): H₅ thiazole; 7.12: CH═CH--CH₂ ; 7.32 (m): NH₂ ; 7.97:aromatic H's; 8.26 (d)-9.08 (d): thieno (2,3-b) pyridine; 9.54 (s)-9.64(s): NH-CO; 9.82: mobile H's.

EXAMPLE 79 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro-3,4-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-1-methyl-pyrrolidinium

Stage A:1-(3-[7β-[[[[[1-[2,5-difluoro-3,4bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4-methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-1-methyl-pyrrolidiniumiodide

Using the procedure of Stage A of Example 68, 256 mg of the iodatedderivative in 5 ml of ether and 1 ml of methylene chloride were reactedand homogenization was carried out using ultrasound and 0.10 ml of1-methyl pyrrolidine were added to obtain 208 mg of the expected productwith Rf=0.2 (methylene chloride--methanol 95-5)

NMR spectrum: CDCl₃ 300 MHz.

2.25 (1): ##STR274## 3.67 (1): (CH₂ --CH₂ --.sup.⊕ N--Me; 3.21 (s,resolved): CH₃ --N₊ <; 3.33-3.35: CH₃ --C--O; 3.55-4.00: OCH₂ CH₂ O, CH₂S; 3.80 (s): CH₃ OAr; 4.24 (m)-4.50 (m): ═CH--CH₂ N.sub.⊕ ; 5.00 (d,resolved: H₆ cephalosporin; 5.25 (m): OCH₂ O, CO₂ CH₂ Ar; 5.78 (dd)-5.92(dd): H₇ cephalosporin; 6.05 (m)-6.19 (m): ═CH--CH₂ ΔE; 6.77 (s,resolved): H₅ thiazole; 6.91 (m): CO₂ CHPh₂, H of the fluorophenyl;7.00-7.40: aromatic H's, CH═CH--CH₂ ; 7.96(d) 8.20 (d): CONHCH; 6.36 (s,resolved): ##STR275##

Stage B: Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)((carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-1-methyl-pyrrolidinium

Using the procedure of Stage B of Example 68, 295 mg of the product ofStage A and 5 ml of trifluoroacetic acid with 10% anisole were reactedto obtain 130 mg of the expected product.

NMR spectrum: DMSO 300 MHz 2.09 (sl): pyrrolidine; 2.96 (s)-2.99 (s):methyl pyrrolidine; 4.01 (m)-4.10 (m): pyrrolidine and CH₂ --N.sup.⊕ ;5.21 (m): H₆ cephalosporin; 5.45-5.95: H₇ cephalosporin; 5.63 (s)-5.64(s): Ar--CH--CO₂ ; 6.16 (m): CH═CH--CH₂ ; 6.73 (dd): H of thefluorophenyl; 6.80-6.87: H₅ thiazole; 7.04 (d, J=15): CH═CH--CH₂ ; 7.30(1): NH₂ ; 9.67-9.89: mobile H's

EXAMPLE 80 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-6,7-dihydro-pyrindinium

Using the procedure of Stages A and B of Example 68,700 mg of theiodated derivative prepared above and the appropriate amine were reactedto obtain 604 mg of the intermediate quaternary salt, 600 mg of whichwere reacted with 6 ml of trifluoroacetic acid with 10% anisole toobtain 323 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 2.24 (m)-3.14-3.34 (m): indane; 3.53(dl)-3.74 (dl): the CH₂ S's; 5.10 (m)-5.16 (m): H6; 5.58 (s)-5.60 (s):O--CH--CO; 5.72 (m): H7; 6.68 (m): fluorophenyl; 6.77 (s)-6.78 (s): H₅thiazole; 6.86 (dl): CH═CH--CH₂ ; 7.91 (dd)-8.43 (d)-8.75 (d):pyrindane.

EXAMPLE 81 Internal salt of (6R-(3-(E)6α,7β-(Z)))-2-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-isoquinolinium

Using the procedure of Stages A' and B of Example 68,700 mg of theiodated derivative prepared above and the appropriate amine were reactedto obtain 584 mg of the intermediate quaternary salt, 580 mg of whichwere reacted with 6 ml of trifluoroacetic acid with 10% anisole toobtain 312 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.45 (m): the CH₂ S's; 5.09 (m)-5.15 (d,resolved): H₆ ; 5.58 (s)-5.60 (s): C--CH--CO; 5.56 (d, resolved): CH₂--N.sup.⊕ ; 5.75 (m): H₇ ; 6.69 (m): fluorophenyl; 6.78 (s): H₅thiazole; 6.54 (m): CH═CH--CH₂ ; 7.09 (d, resolved): CH═CH--CH₂ ; 8.09to 10.06: isoquinoline.

EXAMPLE 82 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1azabicyclo-[4,2,0]oct-2-en-3-yl)-2-propenyl)-1-methyl-pyrrolidinium

Using the procedure of Stages A and B of Example 68, 923 mg of theiodated derivative prepared above and the appropriate amine were reactedto obtain 661 mg of the intermediate quaternary salt, 652 mg of whichwere reacted with 6 ml of trifluoroacetic acid with 10% anisole toobtain 317 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 2.10 (sl)-3.45-(sl): pyrrolidine; 2.99 (sl):N.sup.⊕ --CH₃ ; 3.45 (m): the CH₂ S's; 5.12 (d)-5.16 (d): H₆ ; 5.58(s)-5.60 (s): O--CH--CO; 4.10 (sl): CH₂ --N.sup.⊕ ; 5.75 (m): H₇ ; 6.69(m): H of the fluorophenyl; 6.68 (s, resolved): H₅ thiazole; 6.12 (m):CH═CH--CH₂ ; 7.03 (d, resolved): CH═CH--CH₂.

EXAMPLE 83 Internal salt of (6R-(3-(E)6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno(2,3-b) pyridinium

Using the procedure of Stages A and B of Example 68, 700 mg of theiodated derivative prepared above and the appropriate amine were reactedto obtain 565 mg of the intermediate quaternary salt, 537 mg of whichwere reacted with 6 ml of trifluoroacetic acid with 10% anisole toobtain 290 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.54 (d)-3.76 (d): the CH₂ S's; 5.11(d)-5.16 (d): H₆ ; 5.58 (s)-5.59 (s): O--CH--CO; 5.67 (m): CH₂ --N.sup.⊕; 5.74 (m): H₇ ; 6.68 (m): fluorophenyl; 6.77 (s, resolved): H₅thiazole; 6.22 (m): CH═CH--CH₂ ; 7.13 (d, resolved, J═15): CH═CH--CH₂ ;7.89-8.14-8.28-9.28-9.71: thieno (2,3-b) pyridine.

EXAMPLE 84 Internal salt of (6R-(3-(E)6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-4-methylthiopyridinium.

Using the procedure of Stages A and B of Example 68,800 mg of theiodated derivative prepared above and the appropriate amine were reactedto obtain 660 mg of the intermediate quaternary salt, which was reactedwith 6 ml of trifluoroacetic acid with 10% anisole to obtain 305 mg ofthe expected product.

NMR Spectrum: DMSO 300 MHz. 3.72 (s): CH₃ --S--; 3.47 (d)-3.69 (d): theCH₂ S's; 5.11 (d)-5.16 (d): H₆ ; 5.58 (s)-5.60 (s): O--CH--CO; 5.22 (m):CH₂ -N.sup.⊕ ; 5.74 (m): H₇ ; 6.69 (m): H of the fluorophenyl; 6.78 (s,resolved): H₅ thiazole; 6.22 (m): CH═CH--CH₂ ; 6.96 (d, resolved):CH═CH--CH₂ ; 7.95 (d)-8.69 (s, resolved): pyridine.

EXAMPLE 85 Internal salt of(6R-(3-(E)-6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-pyridinium

Using the procedure of Stages A and B of Example 68,700 mg of theiodated derivative prepared above and the appropriate amine were reactedto obtain 563 mg of intermediate quaternary salt, 546 mg of which werereacted with 6 ml of trifluoroacetic acid with 10% anisole to obtain 280mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.45 (m): the CH₂ S's; 5.11 (d)-5.16 (d): H₆; 5.58 (s)-5.60 (s): O--CH--CO; 5.41 (sl): CH₂ --N.sup.⊕ ; 5.74 (m): H₇; 6.69 (m): H of the fluorophenyl; 6.78 (s, resolved): H₅ thiazole; 6.27(m): CH═CH--CH₂ ; 7.00 (d, resolved, J=15.5): CH═CH--CH₂ ; 8.04 (t)-8.18(t)-9.75 (sl): pyridine; 9.57 (m)-9.27 (s)-9.77 (s)-9.88 (s): mobileH's.

EXAMPLE 86 Internal salt of(6R-(3-(E)-6α,7β-(Z)))-3-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-1-methyl-1H-benzimidazolium

Using the procedure of Stages A and B of Example 68,700 mg of theiodated derivative prepared above and the appropriate amine were reactedto obtain 447 mg of the intermediate quaternary salt, 440 mg of whichwere reacted with 6 ml of trifluoroacetic acid with 10% anisole toobtain 247 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 4.09: N-CH₃ (1-methyl 1H-benzimidazole);3.54 (d)-3.76 (d): the CH₂ S's; 5.11 (d)-5.14 (d, resolved): H₆ ; 5.58(s)-5.59 (s): O--CH--CO; 5.30 (m): CH₂ --N.sup.⊕, 5.74 (m): H₇ ; 6.68(m): fluorophenyl; 6.77 (s)-6.78 (s): H₅ thiazole; 6.22 (m): CH═CH--CH₂; 7.08 (d, resolved): CH═CH--CH₂ ; 7.7 (m)-8.02 (m)-9.70 (s):benzimidazole; 9.6 (m) to 9.90: mobile H's.

EXAMPLE 87 Internal salt of(6R-(3-(E)-6α,7β-(Z)))-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo-(2,1-b)-thiazolium

Using the procedure of Stages A and B of Example 68,500 mg of theiodated derivative prepared above and the appropriate amine were reactedto obtain 130 mg of the intermediate quaternary salt. 330 mg of theproduct prepared in an identical manner were reacted with 5 m oftrifluoroacetic acid with 10% anisole to obtain 174 mg of the expectedproduct.

NMR spectrum: DMSO 300 MHz. 3.54 (d)-3.76 (d): the CH₂ S's; 5.11(d)-5.14 (d, resolved): H₆ ; 5.58 (s)-5.59 (s): O--CH--CO; 5.30 (m): CH₂--N.sup.⊕ ; 5.74 (m): H₇ ; 6.68 (m): fluorophenyl; 6.77 (s)-6.78 (s): H₅thiazole; 6.22 (m): CH═CH--CH₂ ; 7.08 (d, resolved): CH═CH--CH₂ ; 7.23(d)-8.03 (s)-8.23 (s)-8.28 (d, resolved): imidazo (2,1-b) thiazole; 9.68(m) to 9.90: mobile H's.

EXAMPLE 88 Internal salt of(6R-(3-(E)-6α,7β-(Z)))-3-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thiazolium

Using the procedure of Stages A and B of Example 68, 450 mg of theiodated derivative prepared above and the appropriate amine were reactedto obtain 130 mg of the intermediate quaternary salt. which was reactedwith 5 ml of trifluoroacetic acid with 10% anisole to obtain 63 mg ofthe expected product.

NMR spectrum: DMSO 300 MHz. 3.54 (d)-3.76 (d): the CH₂ S's; 5.13 (d,resolved): H₆ ; 5.58 (s)-5.59 (s): O--CH--CO; 5.33 (m): CH₂ --N.sup.⊕ ;5.74 (m): H₇ ; 6.68 (m): fluorophenyl; 6.79 (s, resolved): H₅ thiazole;6.22 (m): CH═CH--CH₂ ; 7.08 (d, resolved): CH═CH--CH₂ ; 8.36 (m)-8.03(s)-8.51(M)-10.2 (s): thiazole; 9.67 (m) to 9.87: mobile H's.

EXAMPLE 89 Internal salt of(6R-(3-(E)-6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-5,6,7,8-tetrahydro quinolinium

Using the procedure of Stages A and B of Example 68, 300 mg of theiodated derivative prepared above and the appropriate amine were reactedto obtain 212 mg of the intermediate quaternary salt. 230 mg ofidentical product were reacted with 5 ml of trifluoroacetic acid with10% anisole to obtain 143 mg of the expected product.

NMR Spectrum: DMSO 300 MHz. 1.77 (m)-1.91 (m)-2.96 (m)-3.12 (m)-5.38(m): CH₂ quinoline; 3.3 to 3.8 (m): the CH₂ S's; 5.09 (d)-5.15 (d): H₆ ;5.58 (s)-5.60 (s): O--CH--CO; 5.38 (m): CH₂ --N.sup.⊕ ; 5.74 (m): H₇ ;6.69 (m): fluorophenyl; 6.77 (s)-6.78 (s): H₅ thiazole; 6.22 (m):CH═CH--CH₂ ; 6.73 (m): CH═CH--CH₂ ; 7.92 (m)-8.35 (d)-8.85 (d):CH-quinoline; 7.31 (m)-9.58 (d, resolved): mobile H's.

EXAMPLE 90 Internal salt of(6R-(3-(E)-6α,7β-(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-5,6,7,8,9,10,11,12,13,14-decahydrocyclododecab) pyridinium

Using the procedure of Stages A and B of Example 68,300 mg of theiodated derivative prepared above and the appropriate amine were reactedto obtain 212 mg of the intermediate quaternary salt, 200 mg of whichwere reacted with 5 ml of trifluoroacetic acid with 10% anisole toobtain 60 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 1.42-1.54-1.74-2.50-3.14-3.87:cyclododecane; 3.3 to 3.8 (m): the CH₂ S's; 5.10 (d)-5.15 (d): H₆ ; 5.58(s)-5.60 (s): O--CH--CO; 5.38 (m): CH₂ --N.sup.⊕ ; 5.73 (m): H₇ ; 6.69(m): fluorophenyl; 6.77 (s)-6.78 (s): H₅ thiazole; 6.22 (m): CH═CH--CH₂; 6.73 (m): CH═CH--CH₂ ; 5.13 (d)-7.97 (t)-8.87 (d): pyridine; 9.58 (d,resolved): CH--NH--CO.

EXAMPLE 91 Internal salt of(6R-(3-(E)-6α,7β-(Z)))-5-amino-2-(3(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-1-(3-methoxypropyl)-1H-pyrazolium

Using the procedure of Stages A and B of Example 68,300 mg of theiodated derivative prepared above and the appropriate amine were reactedto obtain 279 mg of the intermediate quaternary salt, 66 mg of whichwere reacted with 1 ml of trifluoroacetic acid with 10% anisole toobtain 17 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.54 (d)-3.76 (d): the CH₂ S's; 5.11 (d):H6; 5.60 (d): O--CH--CO; 4.98 (t): CH₂ --N.sup.⊕ ; 4.73 (m): H₇ ; 6.69(m): fluorophenyl; 6.79 (s, resolved): H₅ thiazole; 6.05 (m): CH═CH--CH₂; 6.69 (m): CH═CH--CH₂ ; 1.77 (sl)-4.17 (t)-3.40 (s): methoxypropyl;7.30-7.33 (s): NH₂ ; 5.86 (d)-8.10 (sl): pyrazole; 9.58: C--NH--CH.

EXAMPLE 92 Internal salt of(6R-(3-(E)-6α,7β-[Z,(S*)]-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-quinolinium

Using the procedure of Stages A and B of Example 68, 4.14 g of theiodated derivative prepared below and the appropriate amine were reactedto obtain 2.79 g of the intermediate quaternary salt, which was reactedwith 70 ml of trifluoroacetic acid with 10% anisole to obtain theexpected product.

NMR spectrum: DMSO 300 MHz. 3.45 (m): the CH₂ S's; 5.08 (s): H₆ ; 5.57(s): O--CH--CO; 5.88 (m): CH₂ --N.sup.⊕ ; 5.73 (dd): H₇ ; 6.67 (m):fluorophenyl; 6.32 (m): CH═CH--CH₂ ; 6.95 (d): CH═CH--CH₂ ; 8.07 (t)1H-9.34 (d) 1H-9.57 (d) and 8.20 to 8.33 (2H)-8.53,(m) 2H: quinoline.

Preparation of4-methoxybenzyl-7β-[[[[[1-[2,3-difluoro-4,5bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)(S*)3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate.

Stage A:[[1-(2,3-difluoro-4,5bis[(2-methoxyethoxy)-methoxy]phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-aceticacid

The aminoxy derivative of Stage H of the preparation of Example 68 wassubjected to a high performance liquid chromatography, followed bystirring for 2 hours under a nitrogen atmosphere and at ambienttemperature with 5.39 g of the appropriate enantiomer and 3.87 g of oxo[2-[(triphenylmethyl)amino]-thiazol-4-yl]-acetic acid in the present of60 ml of methanol. Then, the solvent was eliminated to obtain 8.3 g ofthe expected product.

Stage B:4-methoxybenzyl-7β-[[[[[1-[2,3-difluoro-4,5bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)(S*)]-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2.0]oct-2-en-2-carboxylate

3.67 g of 4-methoxybenzyl-7β-amino-3-[(Z)3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylatehydrochloride (prepared as described in Application EP 0,333,154) and2.04 g of N-ethyl dimethylaminopropyl carbodiimide (EDAC) were added toa solution of 8.29 g of the product of Stage A in 60 ml of methylenechloride and the mixture was cooled to 5° C. The mixture was stirred for15 minutes at 0° C., then for 1 hour while allowing the temperature torise to 20° C. The reaction mixture was poured into a saturated aqueoussolution of sodium chloride, followed by decanting. The organic phasewas dried and the solvent was eliminated under reduced pressure. Theresidue was chromatographed on silica (eluant: CH₂ Cl₂ --AeOEt 9-1) toobtain 8.16 g of the expected product.

Stage C:4-methoxybenzyl-7β-[[[[1-[2,3-difluoro-4,5bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[((Z)(S*)]3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate

2.2 g of sodium and 1 crystal of iodine were added to solution of 6.63 gof the product of Stage B in 66 ml of acetone and the mixture wasstirred for 1 hour at ambient temperature. After evaporating to drynessunder reduced pressure, the dry exact was taken up in methylenechloride, washed with a 10% solution of sodium thiosulfate then withsalt water, followed by drying, then evaporating to dryness underreduced pressure to obtain 6.64 g of the expected product which was usedas is for the following stage.

EXAMPLE 93 Internal salt of(6R-(3-(E)-6α,7β-[(Z)(S*)]-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3,4-trihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno(2,3-b) pyridinium

Using the procedure of Stages A and B of Example 68, 4.14 g of theiodated derivative prepared above and the appropriate amine were reactedto obtain 2.15 g of the intermediate quaternary salt, which was reactedwith 50 ml of trifluoroacetic acid with 10% anisole to obtain theexpected product.

NMR spectrum: DMSO 300 MHz. 3.54 (d)-3.76 (d): the CH₂ S's; 5.11 (d): H₆; 5.58 (s): O--CH--CO; 5.67 (m): CH₂ --N.sup.⊕ ; 5.76 (m): H₇ ; 6.67(dd, J=6.5 and 2): chlorophenyl; 6.78 (s): H₅ thiazole; 6.22 (m):CH═CH--CH₂ ; 7.11 (d J=16): CH═CH--CH.sup.⊕ ; 7.89 (d)-8.28 (d)-and 8 15(t)-9.28 (d)-9.71 (d): thieno (2,3-b) pyridine.

EXAMPLE 94 Internal salt of (6R-(S-(E)-6α,7β-[(Z)(S8)]-1-(3(7-(((2-amino-4-thiazolyl)-(carboxy-(2,5-difluoro 3,4dihydroxyphenyl)-methoxy)-imino)-acetyl)-amino)-2-carboxy-8-oxo-5-thia-1-azabicyclo[-4,2,0]oct-2-en-3-yl)-2-propenyl)-quinolinium

The iodated derivative of Stage A of Example 72, was subjected to a highperformance liquid chromatography and the 2 enantiomers were separated.The operation was carried out as in Stage B of Example 70 with 1.53 g ofthe appropriate enantiomer and 16.5 ml of trifluoroacetic acid with 10%anisole to obtain 645 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 5.14 (m): H6; 5.63 (s)-5.64 (s): O--CH--CO;5.89 (m): CH₂ --N.sup.⊕ ; 5.81 (m): H₇ ; 6.31 (m): CH═CH--CH₂ ; 6.36(m): CH═CH--CH₂ ; 6.69 (dd): difluorophenyl; 8.07 (t)-8.26 (m)-8.53(m)-9.34 (d)-9.58 (d): quinoline.

EXAMPLE 95 Internal salt of (6R-(3-(E)-6α,7β-[Z]-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dichloro 4,5dihydroxyphenyl)-methoxy)-imino)-acetylamino)-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]oct-2-en-3-yl)-2-propenyl)quinolinium

Using the procedure of Stages A and B of Example 68, 850 mg of theiodated derivative prepared below and 0.34 ml of quinoline were reactedto obtain 850 mg of the intermediate quaternary salt, 810 mg of whichwere reacted with 8 ml of trifluoroacetic acid with 10% anisole toobtain 390 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.4-3.7: the CH₂ S's; 5.72 (d): H₆ ; 5.07(d)-5.14 (d): H₇ ; 5.75-5.76 (s): O--CH--CO; 5.88 (m): CH₂ --N.sup.⊕ ;6.33(m): CH═CH--CH₂ ; 6.78 (s)-6.79 (s): H₅ thiazole; 6.93 (s)-6.95 (s):fluorophenyl; 6.97 (m): CH═CH--CH₂ ; 8.07 and 8.26 (d)-8.51 (d) and 8.55(d)-9.34 (d)-9.58 (d): quinoline.

Preparation of4-methoxybenzyl-7β-[[[[[1-[2,3-dichloro-4,5bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3[(Z)3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate.

Stage A: 2,3-dichloro-4,5bis-[(2-methoxyethoxy)-methoxy]benzaldehyde

Using the procedure of Stage B of Preparation 3, 2.21 g of2,3-dichloro-4-hydroxy-5-methoxy-benzaldehyde were reacted to obtain 1.4g of dimethylated product which was reacted with 1.7 ml of chloro(2-methoxyethoxy) methane to obtain 2.6 g of the expected product with aRf=0.25 (CH₂ Cl₂ -AcOEt 9-1)

Stage B: 2,3,dichloro-4,5bis-[(2-methoxyethoxy)-methoxy]-styrylcarboxylate

Using the procedure of Stage B of Example 40, 27.5 g of Stage A, 6.78 gof lithium bromide, 13.8 ml of triphenyl phosphonacetate and 10.36 ml oftriethylamine were reacted to obtain 31.5 g of the expected productmelting at <45° C.

Stage C: 2,3-dichloro-4,5bis-[(2-methoxyethoxy)-methoxy]styrol

Using the procedure of Stage C of Example 40, 20 g of ester of Step Band 88 ml of diisobutylaluminium hydride were reacted to obtain 17.9 gof the expected product melting at 60° C.

Stage D: 2,3-dichloro-4,5bis-[(2-methoxyethoxy)-methoxy](1,2-epoxy)styrol

Using the procedure of Stage D of Example 40, 13.2 g of thee allylicalcohol of Step C and 10.3 g of m-chloro perbenzoic acid were reacted toobtain 13.7 g of the expected product with a Rf =0.25 (AcOEt-cyclohexane6-4)

Stage E:diphenylmehtyl-2,3-dichloro-4,5-bis-[2-methoxyethoxy)-methoxy]-phenyl-chloro-acetate.

a) opening the epoxide

Using the procedure of Example 40, 427 mg of the epoxide, 295 mg ofcupric chloride and 184 mg of lithium chloride were reacted to obtain410 mg of intermediate diol melting at 68° C.

b) oxidation

Using the procedure of Example 40, 1.06 mg of the diol, 1.97 g of sodiumperiodate and 32 mg of ruthenium chloride were reacted to obtain 1.01 gof the desired product.

c) Esterification

8 ml of diphenyldiazomethane were reacted with the above product asindicated in Example 40, to obtain 1.52 g of the expected product withRf=0.25 (cyclohexane-AcOEt 5-5).

Stage F:diphenylmethylaminoxy-2,3-dichloro-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl-acetate

a) Phthalimidoxylation

7.30 g of the product of Stage E, 60 ml of dimethylformamide, 1.27 ofpotassium acetate and 2.13 g of N-hydroxyphthalimide were stirred for 3hours to obtain 8.95 g of intermediate product.

b) Hydrazinolysis

Using the procedure of Example 40, 640 mg of the product above and 0.088ml of hydrazine hydrate were reacted to obtain 505 mg of the expectedproduct with a Rf=0.15 (CH₂ Cl₂ -AcOEt 9-1)

Stage G:[[1-[2,3-dichloro-4,5-bis-[(2-methoxy-ethoxy)methoxy)-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-[(triphenylmethyl)-amino]-thiazol]-4-yl]-aceticacid

Using the procedure of Stage E of Example 1, 5.56 g of the product ofStage F and 3.8 g ofoxo-[2-[(triphenylmethyl)-amino]thiazol]-4-yl]-acetic acid (described inBelgian Application No. 864828) were reacted to obtain 8.9 g of theexpected product.

Stage H:4-methoxybenzyl-7β-[[[[1-[2,3-dichloro-4,5bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamino]-3[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate

Using the procedure of Stage F of Example 1, 1.28 g of the product ofStage G and 0.605 g of4-methoxybenzyl-7β-amino-3-[(Z)3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2carboxylate(EP 0,333,154) were reacted to obtain after chromatography on silica,(eluant: methylene chloride -ether (8-2)), 1.27 g of the desired productwith a Rf=0.25 (CH₂ Cl₂ -ether 9-1)

EXAMPLE 96 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dichloro-4,5-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo-(1,2-a)pyridinium

Using the procedure of Stages A and B of Example 68, 700 mg of theiodated derivative prepared below and 0.25 ml of imidazo (1,2-a)pyridine were reacted to obtain 550 mg of the intermediate quaternarysalt of which were reacted with 5 ml of trifluoroacetic acid with 10%anisole to obtain 210 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.4-3.7: the CH₂ S's; 5.04-5.08 (d): H₇ ;5.29 (m): CH₂ --N.sup.⊕ ; 5.72 (d): H₆ ; 5.77 (s): O--CH--CO; 6.20:CH═CH--CH₂ ; 6.79-6.80 (s): H₅ thiazole; 6.87 (d, resolved): CH═CH--CH₂; 6.94 (s)-6.95 (s): chlorophenyl; 7.58 (t)-8.05-8.19-8.36-8.28 and8.44: imidazo (1,2-a) pyridine.

EXAMPLE 97 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dichloro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-6,7-dihydro-5H-pyrindinium

Using the procedure of Stages A and B of Example 68,850 mg of theiodated derivative prepared above and 0.34 ml of cyclopentylpyridinewere reacted to obtain 730 mg of the intermediate quaternary salt, 710mg of which were reacted with 0.7 ml of trifluoroacetic acid with 10%anisole to obtain 318 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 2.24-3.75 and 3.35: indane; 3.4-3.7: the CH₂S's; 5.09-5.16: H₇ ; 5.33 (d): CH₂ --N.sup.⊕ ; 5.74: H₆ ; 5.77-5.78:O--CH--CO; 6.13: CH═CH--CH₂ ; 6.79-6.80: H₅ thiazole; 6.87 (d,resolved): CH═CH--CH₂ ; 6.95 (s)-6.96 (s): chlorophenyl; 7.82-8.43-8.76(d): pyridine.

EXAMPLE 98 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,3-dichloro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno(2,3-b)pyridinium

Using the procedure of Stages A and B of Example 68,710 mg of theiodated derivative prepared above and 325 mg of thienopyridine werereacted to obtain 740 mg of the intermediate quaternary salt, 700 mg ofwhich were reacted with 7 ml of trifluoroacetic acid with 10% anisole toobtain 265 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.67: CH₂ --N.sup.⊕ ; 5.10-5.17 (d): H₇ ;5.77: H₆ and O--CH--CO; 6.26 (m): CH═CH--CH₂ ; 6.78 (s): H₅ thiazole;6.84 (s): chlorophenyl; 7.13 (d, J=15.5): CH═CH--CH₂ ; 7.88 (d)-8.15(d)-8.28 (d)-9.08 (d)-9.22 (d): thienopyridine.

EXAMPLE 99 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,6-dichloro-3,4-dihydroxy-phenyl)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)quinolinium

Using the procedure of Stages A and B of Example 68,450 mg of theiodated derivative prepared below and 386 mg of quinoline were reactedto obtain 434 mg of the intermediate quaternary salt, 427 mg of whichwere reacted with 4 ml of trifluoroacetic acid with 10% anisole toobtain 195 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.52: the CH₂ S's; 3.71 (s): methoxyphenyl;5.17 (m): H₆ ; 5.69-5.76: H₇ ; 5.88 (m): CH₂ --N.sup.⊕ ; 6.17-6.20 (s):O--CH--CO; 6.38 (m): CH═CH--CH₂ ; 6.72 (s)-6.78 (s): H₅ thiazole; 6.97:CH═CH--CH₂ ; 8.06-8.26-8.53 and 9.47: quinoline.

Preparation of4-methoxybenzyl-7β-[[[[[1-[2,6-dichloro-4,5bis-[(2-methoxy-ethoxy)-methoxy]-3-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate.

Stage A: 2,6-dichloro-3,4,5-trimethoxy-benzaldehyde

442 ml of as solution of chlorine (37.13 g) in acetic acid were added to50 g of trimethoxy aldehyde in 200 ml of acetic acid. After stirring for16 hours at ambient temperature, 500 ml of water were added and themixture was stirred for 1 hour, followed by filtering. The precipitatewas taken up in cyclohexane dried and the solvent was eliminated underreduced pressure to obtain 37.1 g of the expected product melting at 76°C.

Stage B: diphenylmethylaminoxy[2,6-dichloro-3-methoxy-4,5-bis-[2-methoxyethoxy)-methoxy]-phenyl]-acetate

Using the procedure of Stages B to F of Example 40 the aldehyde obtainedin Stage A above was reacted to obtain the expected product.

Stage C:[[[1-[2,6-dichloro,3-methoxy-4,5bis-[-2-methoxy-ethoxy)-phenyl]-2-oxo-2-(diphenylmethoxyl-ethyl]-oxy]-imino]-[2-[triphenylmethyl-amino]-thiazol]-4-yl]-aceticacid

1 g of the product of Stage B was mixed with 10 ml of methanol and after617 mg of oxo-2-[triphenylmethyl-amino]-thiazol]-4-yl]-acetic acid(described in Belgian Patent Application No. 864828) were added, themixture was stirred for 2 hours. The solvent was eliminated underreduced pressure and the residue was taken up in 20 ml of methylenechloride, followed by washing with a 0.1N-hydrochloric acid solution,drying, filtering and evaporating the solvent under reduced pressure toobtain 1.517 g of the expected product with a Rf=0.5 (AcOEt-Et0H 7-3)

Stage D:4-methoxybenzyl-7β-[[[[[2,6-dichloro-3-methoxy-4,5-bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4yl]-acetamido]-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1azabicyclo[4,2,0]oct-2-en-2-carboxylate

0.677 g of 4-methoxybenzyl-7β-amino-3-[(Z)3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate (described in European Patent ApplicationNo. 0,333,154), and 1.48 g of the product of Stage C in 10 ml ofmethylene chloride were stirred cooled to 5° C. and then, 0.327 g of1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDAC) were added. Themixture was stirred for 30 minutes and then the reaction mixture wastreated with 10 ml of potassium hydrogenophosphate in 20 ml of methylenechloride, followed by decanting, washing and drying and evaporating thesolvents to obtain 1.90 g of the expected product with a Rf=0.30[eluant: methylene chloride - ethyl acetate (90-10)].

Stage E:4-methoxybenzyl-7β-[[[[[2,6-dichloro-3-methoxy-4,5bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4yl]-acetamido]-3-[(Z)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate

1.18 g of the product of Stage D in 11 ml of acetone and 0.471 g ofsodium iodide in the presence a crystal of iodine were stirred for onehour at ambient temperature. After elimination of the solvent, theresidue was taken up in methylene chloride and the organic phase iswashed and dried. The solvent was eliminated and the residue waschromatographed on silica (eluant: methylene chloride--methanol 9-1) toobtain 0.908 g of iodated product with a Rf=0.30 (eluant: methylenechloride--methanol 90-10)

EXAMPLE 100 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2,6-dichloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno-(2,3-b)-pyridinium

Using the procedure of Stages A and B of Example 68, 450 mg of theiodated derivative prepared above and 404 mg of thieno-(2,3-b) pyridinewere reacted to obtain 423 mg of the intermediate quaternary salt, 415mg of which were reacted with 4 ml of trifluoroacetic acid with 10%anisole to obtain 193 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.56: the CH₂ S's; 5.19 (d, d): H₆ ; 5.67(m): CH₂ --N.sup.⊕ ; 6.17-6.19 (s): O--CH--CO; 6.30 (m): CH═CH--CH₂ ;7.13 (d): CH═CH--CH₂ ; 7.88-8.27 and 8.14-9.08-9.21 (d): thieno (2,3-b)pyridine.

EXAMPLE 101 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-6,7-dihydro-5H-pyrindinium

Using the procedure of Stages A and B of Example 68, 1 g of the2-chloro-5-methoxy iodated derivative obtained as indicated below and405 mg of cyclopentenopyridine were reacted to obtain 1.14 g of theintermediate quaternary salt, 1.13 g of which were reacted with 11.3 mlof trifluoro-acetic acid with 10% anisole to obtain 682 mg of theexpected product.

NMR spectrum: DMSO 300 MHz. 2.23 (m)-3.14 and 3.36 (m): indane; 3.54 (d,resolved): the CH₂ S's; 3.73 (s)-3.75 (s): CH₃ --O--; 5.2 (d, resolved):H₆ ; 5.33 (dl): CH₂ --N.sup.⊕ ; 5.83 (m): H₇ ; 5.84 (s)-5.86 (s):O--CH--CO; 6.25 (m): CH═CH--CH₂ ; 6.6 (s): chlorophenyl; 6.8 (s): H₅thiazole; 7.91 (m)-8.42 and 8.76 (d): pyridine.

Preparation of4-methoxybenzyl-7β-[[[[[1-[2-chloro-3,4bis-[(2-methoxy-ethoxy)-methoxy]-5-methoxy]-phenyl]-2-oxo-2-(diphenyl-methoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4yl]-acetamido]-3-[(Z)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate.

Using the procedure of the preparation of Example 40, Stage E, the[2-chloro-3,4-bis-[(2-methoxyethoxy)-methoxy]-5-methoxy-(1,2-epoxy)-styrol (isomer B) of Stage D wasreacted to obtain the desired product.

EXAMPLE 102 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-2-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-isoquinolinium

Using the procedure of Stages A and B of Example 68, 1 g of the2-chloro-5-methoxy iodated derivative obtained above and 439 mg ofisoquinoline were reacted to obtain 1.03 g of the intermediatequaternary salt, 1.02 g of which were reacted with 10.2 ml oftrifluoroacetic acid with 10% anisole to obtain 645 mg of the expectedproduct.

NMR Spectrum: DMSO 300 MHz. 3.5 to 3.9: the CH₂ S's; 3.73 (s)-3.75 (s):CH₃ --O--Φ; 5.27 (m): H₆ ; 5.52 (dl): CH₂ --N.sup.⊕ ; 5.81 (m): H7; 5.8(s)-5.85 (s): O--CH--CO; 6.38 (m) : CH═CH--CH₂ ; 6.8 (s)-6.83 (s): H₅thiazole; 8.09 (t)-8.28-8.61 (d)-8.74 (d)-8.37 (d)-8.54 (d) and 10.06(s): isoquinoline.

EXAMPLE 103 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-1-methylpyrrolidinium.

Using the procedure of Stages A and B of Example 68, 1 g of the2-chloro-5-methoxy iodated derivative above and 362 ml ofN-methyl-pyrrolidine were reacted to obtain 940 mg of the intermediatequaternary salt, 930 mg of which were reacted with 9.5 ml oftrifluoroacetic acid with 10% anisole to obtain 570 mg of the expectedproduct.

NMR spectrum: DMSO 300 MHz. 2.09 (m)-2.98 (m)-3.4 (m): 1-methylpyrrolidine; 3.75 (s)-3.76 (s): CH₃ --O--Φ; 5.22 (d, resolved): H₆ ;4.09 (dl): CH₂ --N.sup.⊕ ; 5.84 (m): H₇ ; 5.86 (s)-5.88 (s): O--CH--CO;6.18 (m): CH═C--CH₂ ; 6.62 (s)-6.63 (s): chlorophenyl; 6.84 (s)-6.87,(s): H₅ thiazole; 7.02 (d1, J=15.5): CH═CH--CH₂.

EXAMPLE 104 Internal salt of(2(E)-3-(6R-6α,7β[(Z)]-N(2-amino-2-oxoethyl)-3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-N,N-dimethyl-2-propen-1-aminium

Using the procedure of Stages A and B of Example 68, 1 g of the2-chloro-5-methoxy iodated derivative above and 69.4 mg ofdimethylaminoacetamide were reacted to obtain 968 mg of the intermediatequaternary salt, 957 mg of which were reacted with 9.6 ml oftrifluoroacetic acid with 10% anisole to obtain 698 mg of the expectedproduct.

NMR spectrum: DMSO 300 MHz. 3.78 (s): N.sup.⊕ (CH₃)₂ ; 3.5 to 3.95 (m):the CH₂ S's; 3.75 (s)-3.76 (s): CH₃ --O--φ; 5.23 (d, resolved): H₆ ;3.78 (s): CH₂ --N.sup.⊕ ; 5.83 (m): H₇ ; 5.86 (s)-5.88 (s): O--CH--CO;6.14 (m): CH═CH--CH₂ ; 6.61 (s)-6.62 (s): chlorophenyl; 6.83 (s)-6.86(s) : H₅ thiazole; 7.02: CH═CH--CH₂ ; 7.67 (51)-7.93 (sl): CONH₂ ; 9.54.(d)-9.65 (d): CO--NH--CH.

EXAMPLE 105 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-pyridinium.

Using the procedure of Stages A and B of Example 68, 1 g of the2-chloro-5-methoxy iodated derivative above and 275 mg of pyridine werereacted to obtain 1.02 g of the intermediate quaternary salt, 1.01 g ofwhich were reacted with 10 ml of trifluoroacetic acid with 10% anisoleto obtain 560 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.5 to 3.8: the CH₂ S's; 3.73 (s)-3.75 (s):CH₃ --O--Φ; 5.2 (d, resolved) H₆ ; 5.41 (d): CH₂ --N.sup.⊕ ; 5.8: H₇ ;5.85 (s)-5.86 (s): O--CH--CO; 6.31 (m): CH ═CH--CH₂ ; 7.0: CH═CH--CH₂ ;8.18 (m)-8.63 (t)-9.05 (m): pyridine.

EXAMPLE 106 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-4-(methylthio)pyridinium

Using the procedure of Stages A and B of Example 68, 1 g of the2-chloro-5-methoxy iodated derivative above and 500 mg of methylthiopyridine were reacted to obtain 1.003 mg of the intermediate quaternarysalt, 998 mg of which were reacted with 10 ml of trifluoroacetic acidwith 10% anisole to obtain 656 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 2.71 (s): S--CH₃ ; 3.54 (d)-3.67 (m): theCH₂ S's; 3.73 (s)-3.76 (s): CH₃ --O--Φ; 5.21: H₆ ; 5.81: CH₂ --N.sup.⊕and H₇ ; 6.99 (d, J=15.5): CH═CH--CH₂ ; 6.81 (s)-6.83 (s): chlorophenyl;6.61 (s): H₅ thiazole; 7.95 (d)-8.69 (d): pyridine.

EXAMPLE 107 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-3-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]oct-2-en-3-yl)-2-propenyl)-1-methyl-1H-benzimidazolium

Using the procedure of Stages A and B of Example 68, 1 g of the2-chloro-5-methoxy-iodated derivative above and 360 mg ofmethylimidazobenzene were reacted to obtain 1.04 g of the intermediatequaternary salt, 1.03 g of which were reacted with 10 ml oftrifluoroacetic acid with 10% anisole to obtain 648 mg of the expectedproduct.

NMR spectrum: DMSO 300 MHz. 3.55 (d, resolved)-3.67 (m): the CH₂ S's;3.72 (s)-3.74 (s): CH₃ --O--Φ; 5.20 (m): H₆ ; 5.20 (d): CH₂ --N.sup.⊕ ;5.80 (m): H₇ ; 5.83 (s)-5.85 (s): --O--CH--CO; 6.27 (m)-7.08 (d,resolved): CH═CH--CH₂ ; 6.8 (s)-6.84: chlorophenyl; 6.6 (m): H₅thiazole; 7.71 (m)-8.03-9.7 (s) resolved): benzimidazole.

EXAMPLE 108 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-7-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thieno-(2,3-b)pyridinium

Using the procedure of Stages A and B of Example 68, 1 g of the2-chloro-5-methoxy iodated above and 400 μl of thieno (2,3-b) pyridinewere reacted to obtain 991 mg of the intermediate quaternary salt, 976mg of which were reacted with 10 ml of trifluoroacetic acid with 10%anisole to obtain 683 mg of the expected product.

NMR spectrum: DMSO 300 MHz.

3.58 (d): the CH₂ S's; 3.74 (m): CH₃ --O--Φ; 5.21 (m): H₆ ; 5.68 (d):CH₂ --N.sup.⊕ ; 5.84 (m): H₇ ; 6.30 (m): CH═CH--CH₂ ; 6.84 (s)-6.88:chlorophenyl and H₅ thiazole; 7.89 (d)-8.29 (d)-8.15 (dd)-9.09 (d)-9.21(d): thieno pyridine.

EXAMPLE 109 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-3-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-thiazolium

Using the procedure of Stages A and B of Example 68, 1 g of the2-chloro-5-methoxy iodated above and 250 μl of thiazole were reacted toobtain 924 mg of intermediate quaternary salt, which was reacted with9.3 ml of trifluoroacetic acid with 10% anisole to obtain 617 mg of theexpected product.

NMR Spectrum: DMSO 300 MHz. 3.60 (d, resolved)-3.79 (masked): the CH₂S's; 3.75 (s, resolved): CH₃ --O--Φ; 5.21 (d, resolved): H₆ ; 5.33 (s):CH₂ --N.sup.⊕ ; 5.82 (m): H₇ ; 5.85 (s)-5.87: O--CH--CO; 6.25 (m):CH═CH--CH₂ ; 6.67 (s): chlorophenyl; 6.84 (s)-6.87: H₅ thiazole; 8.37(m)-8.52 (d)-10.21: thiazole.

EXAMPLE 110 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-3-(aminocarbonyl)pyridinium

Using the procedure of Stages A and B of Example 68, 1 g of the2-chloro-5-methoxy iodated above and 360 mg of nicotinamide were reactedto obtain 993 mg of intermediate quaternary salt, 980 mg of which werereacted with 10 ml of trifluoroacetic acid with 10% anisole to obtain611 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.55 to 3.8: the CH₂ S's and CH₃ --O--Φ;5.21 (m): H₆ ; 5.47 (d): CH₂ --N.sup.⊕ ; 5.83 (m): H7; 5.88 (s,resolved): O--CH--CO; 6.32 (m): CH═CH--CH₂ ; 6.60 (s): chlorophenyl;6.87 (s, resolved): H₅ thiazole; 8.29 (dd)-8.97 (d)-9.17 (d)-9.47 (s):3aminocarbonyl pyridine.

EXAMPLE 111 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-pyridaziniu

Using the procedure of Stages A and B of Example 68, 735 mg of the2-chloro-5-methoxy iodated derivative above and 60 mg of pyridazine werereacted to obtain 730 mg of intermediate quaternary salt, 720 mg ofwhich were reacted with 7.2 ml of trifluoroacetic acid with 10% anisoleto obtain 470 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.5 to 3.7: the CH₂ S's; 3.74 (s)-3.75 (s):CH₃ --O--Φ; 5.22 (d, resolved): H₆ ; 5.61 (d): CH₂ --N.sup.⊕ ; 5.82 (m):H₇ ; 5.84 (s)-5.86 (s): O--CH--CO; 6.30 (m): CH═CH--CH₂ ; 6.61 (s):chlorophenyl; 6.82 (s)-6.85 (s): H₅ thiazole; 8.63 (m)-8.75 (m)-9.65 (m)2H: pyridazine.

EXAMPLE 112 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]-1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-3-carboxypyridinium

Using the procedure of Stages A and B of Example 68,735 g of the2-chloro-5-methoxy iodated derivative above and 150 mg of diphenylmethylester of nicotinic acid were reacted to obtain 480 mg of intermediatequaternary salt, 470 mg of which were reacted with 4.17 ml oftrifluoroacetic acid with 10% anisole to obtain 243 mg of the expectedproduct.

NMR spectrum: DMSO 300 MHz. 3.4 to 3.80 (m complex): the CH₂ S's; 3.74(s)-3.75 (s): CH₃ --O--Φ; 5.21 (dd): H₆ ; 5.5 (m): CH₂ --N.sup.⊕ ; 5.82(m): H₇ ; 5.83 (s)-5.85 (s): O--CH--CO; 6.31 (m): CH═CH--CH₂ ; 6.79(sl)-6.82 (sl): chlorophenyl; 6.61 (s): H₅ thiazole; 8.29 (m)-9.0(d)-9.22 (d)-9.58 (s): 3-carboxy pyridine.

EXAMPLE 113 Internal salt of (2-(E)-3-(6R-6α,7β-[(Z)]3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-N,N-dimethyl-N-(2-hydroxy-2-oxoethyl)-2-propen-1-aminium

Using the procedure of Stages A and B of Example 68, 800 g of the2-chloro-5-methoxy iodated derivative above and 177 mg of diphenylmethylester of N,N-dimethyl glycine were reacted to obtain 928 mg ofintermediate quaternary salt, 875 mg of which were reacted with 8.8 mlof trifluoroacetic acid with 10% anisole to obtain 426 mg of theexpected product.

NMR spectrum: DMSO 300 MHz. 3.17 (s): (CH₃)₂ N.sup.⊕ ; 3.76 (s): CH₃--O--, 4.27 (s): CH₂ --N.sup.⊕ --CH₂ --CO; 5.22 (m): H₆ ; 4.27 (s): CH₂--N.sup.⊕ ; 5.82 (m): H₇ ; 5.86 (s)-5.87 (s): O--CH--CO; 6.16 (m):CH═CH--CH₂ ; 6.61 (s)-6.62 (s): chlorophenyl; 6.8 (s)-6.85 (s): H₅thiazole.

Preparation of the diphenylmethyl ester of N,N-dimethyl glycine.

2. g of N,N-dimethyl-glycine were dissolved in 19.4 ml of N hydrochloricacid and then after 76.3 ml of a 0.38 M/l solution of diphenyldiazomethane in either were added, 24 ml of methanol were added. Themixture was stirred for 1 hour at ambient temperature, followed byalkalinizing to a pH=10 by the addition of 32 ml of N-sodium hydroxide.The mixture was stirred for 5 minutes and after-extracting with ether,drying and elimination the solvent under reduced pressure, the-residuewas chromatographed on silica (eluant: CHCl₂ with 10% ethyl acetate then8% methanol) to obtain 2.173 g of the expected product.

EXAMPLE 114 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl-4-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)-ethyl-pyridinium

Using the procedure of Stages A and B of Example 68, 735 mg of the2-chloro-5-methoxy iodated derivative above and 117 mg of4-(2-(2-methyl-5-nitro-(1H)-imidazol-1-yl)-ethyl)-pyridine were reactedto obtain 768 mg of intermediate quaternary salt, 758 mg of which werereacted with 7.6 ml of trifluoroacetic acid with 10% anisole to obtain503 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 2.34 (s): CH₃ 2-methylimidazole; 338 (t):--CH₂ --CH₂ ; 3.59 (m): the CH₂ S's; 3.75 (m): CH₃ --O--Φ; 4.64: CH₂--CH₂ -imidazole; 5.21 (d, resolved): H₆ ; 5.36 (dt): CH₂ --N.sup.⊕ ;5.83 (m): H7; 5.83 (s)-5.85: O--CH--CO; 6.27 (m): CH═C--CH₂ ; 6.61 (s):chlorophenyl; 6.8 (s)-6.83: H₅ thiazole; 8.06 (d)-8.98 (d): pyridine;8.08 (s):CH imidazole.

EXAMPLE 115 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-3,4-dihydroxy)-5-methoxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-4-(3-(1-methyl-pyridinium-4-yl)-propyl)-pyridinium

Using the procedure of Stages A and B of Example 68,200 mg of the2-chloro-5-methoxy iodated derivative above and 46 mg of 4-(3(1-methylpyridini-4-yl) pyridine were reacted to obtain 128 mg of intermediatequaternary salt, 120 mg of which were reacted with 1.2 ml oftrifluoroacetic acid with 10% anisole to obtain 77 mg of the expectedproduct.

NMR spectrum: DMSO 300 MHz. 2.08 (m)-2.94 (m): propyl pyridine; 3.5 (m):the CH₂ S's; 3.73 (s)-3.74 (s): CH₃ --O--φ; 4.29 (s): 1--CH₃ -pyridine;5.2 (d, resolved): H_(6;) 5.35 (d): CH₂ N.sup.⊕ ; 5.87 (m): H7; 5.82(s)-5.84 (s): O--CH--CO; 6.3 (m): CH═CH--CH₂ ; 8.0 (d)-8.06 (dt)-8.88(d)-8.95 (d): pyridine.

Preparation of 4-(3-(1-methylpyridin-4-yl)-propyl)-pyridine

378 mg of trimethylene bipyridine were dissolved in 3.8 ml of methylenechloride and then 118 μl of methyl iodide were added. The mixture wasstirred for 2 hours at ambient temperature, followed by filtering andevaporating the solvent under reduced pressure. The residue waschromatographed on silica (eluant: methylene chloride--methanol 92-8) toobtain 170 mg of the expected product.

EXAMPLE 116 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(-4,5-dihydroxy)-3-fluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo(1,2-a)pyridinium

Using the procedure of Stages H and I of Example 3, 700 mg of theiodated derivative of Stage G of Example 3 and 254 ml of imidazo (1,2-a)pyridine were reacted to obtain 713.5 mg of intermediate quaternarysalt, 703 mg of which were reacted with. 7 ml of trifluoroacetic acidwith 10% anisole to obtain 364 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.69 (m): the CH₂ S's; 5.15 (m): H₆ ; 5.29(masked): CH₂ --N.sup.⊕ ; 5.77 (m): H₇ ; 5.53 (d, resolved): O--CH--CO;6.24 (m): CH═CH--CH₂ ; 6.73 to 6.76 3H (s): H₅ thiazole andfluorophenyl; 6.88 (d, resolved): CH═CH--CH₂ ; 7.05 (t)-8.05 (t)-8.18(d)-8.95 (d)-8.28 (m)-8.43 (sl): imidazopyridine.

EXAMPLE 117 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(4,5-dihydroxy)-3-fluorophenyl)methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-6,7-dihydro-5H-pyrindinium

Using the procedure of Stages H and I of Example 3,700 mg of the productof Stage G of Example 3 and 293 ml of cyclopentyl (b) pyridine werereacted to obtain 668.4 mg of intermediate quaternary salt, 657 mg ofwhich were reacted with 7 ml of trifluoroacetic acid with 10% anisole toobtain 369 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 2.23 (m)-3.14 (m)-3.36 (m): indane; 3.53(dl)-3.74 (dl): the CH₂ S's; 5.16 (resolved): H₆ ; 5.3 to 5.35: CH₂--N.sup.⊕ and O--CH--CO; 5.76 (m): H₇ ; 6.22 (m): CH═CH--CH₂ ; 6.73 to6.80: H₅ thiazole and fluorophenyl; 6.87 (d,1): CH═CH--CH₂ ; 7.91(dd)-8.42 (d)-8.95 (d): pyridine.

EXAMPLE 118 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-4,5-dihydroxyphenyl-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-8-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo (1,2-a)-pyridinium

Using the procedure of Stages A and B of Example 68,685 mg of theiodated derivative obtained below and 246 ml of imidazo (1,2-a) pyridinewere reacted to obtain 541 mg of intermediate quaternary salt, 657 mg ofwhich were reacted with 5 ml of trifluoroacetic acid with 10% anisole toobtain 304 mg of the expected product.

NMR spectrum: DMSO 300 MHz. 3.69 (m): the CH₂ S's; 5.13 (d, resolved):H₆ ; 5.21 (s): O--CH--CO; 5.29 (sl): CH₂ N.sup.⊕ ; 5.75 (m): H₇ ; 6.22(m): CH═CH--CH₂ ; 6.75 to 6.92: CH═CH--CH₂, chlorophenyI and H₅thiazole; 8.28 (sl)-8.44 (sl): imidazole; 7.58 (t)-8.06 (t)-8.20(d)-8.96 (d): pyridine.

Preparation of4-methoxybenzyl-7β-[[[[[1-[2-chloro-4,5bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3[(Z)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate.

Stage A: 2-chloro-4,5-dihydroxy-benzaldehyde

Using the procedure of Preparation 4, Stage A, 37.3 g of2-chloro-vaniline were reacted to obtain 32.7 g of expected product isobtained.

Stage B: 2-chloro-4,5-bis-[2-methoxyethoxy)-methoxy]benzaldehyde

Using the procedure of Preparation 4, Stage B, 32.7 g of the product ofStage A and 79 ml of diisopropylethylamine were reacted to obtain 50.7 gof the expected product.

Stage C: 2-chloro-4,5-bis-[(2-methoxyethoxy)-methoxy]-styryl-carboxylate

Using the procedure of Stage B of Example 40, 50.7 g of the product ofStage B were reacted to obtain 60.2 g of the expected crude product.

Stage D: 2-chloro-4,5-bis-[(2-methoxyethoxy)-methoxy]-styrol

Using the procedure of Stage C of Example 40, 60.8 g of the ester ofStage C and 293 ml of a molar solution of diisobutyl-aluminum hydride inhexane were reacted to obtain 18.5 g of the expected product.

Stage E: 2-chloro-4,5-bis-[(2-methoxyethoxy)-methoxy]-1,2-epoxy)-styrol

19 g of vanadylacetylacetonate in solution of 50 ml of methylenechloride were cooled to 0° C. and 3.5 ml of terbutyl hydroperoxide in atoluene solution (3M/l) were added over 30 minutes. The mixture wasstirred for 20 minutes at 0° C. and 2.63 g of the product of Stage D insolution in 10 ml of methylene chloride were added. The reaction mixturewas stirred for 3 hours at ambient temperature and 30 ml of water wereadded. The organic phase was separated and the solvent was eliminatedunder reduced pressure. The residue was chromatographed on silica(eluant: methylene chloride--acetone 8-2) to obtain 21.8 g of theexpected product with a Rf=0.35 (CH₂ Cl₂ -acetone 8-2)

Stage F:diphenylmethyl-[2-chloro-4,5-bis-[(2-methoxyethoxy)-methoxy]-phenyl-chloro-acetate

Using the procedure of Stage E of Example 40, 18 g of the epoxide ofStage E above were reacted to obtain 15.67 g of chlorodiol which wasoxidized with 30.56 g of sodium periodate and 400 mg of hydratedruthenium chloride to obtain 13.59 g of acid which was reacted with 6.36g of diphenyldiazomethane to obtain 18.8 g of the expected product witha Rf=0.3 (CH₂ Cl₂ AcOEt 9-1)

Stage G:diphenylmethylaminoxy,[2-chloro-4,5-bis-[(2-methoxyethoxy)-methoxy]-phenyl]-acetate

Using the procedure of Stage F of Example 40, 18.8 g of the ester ofStage F above 7.33 g of N-hydroxy phthalimide and then 2.36 ml ofhydrazine hydrate were reacted to obtain after chromatographing onsilica (eluant: methylene chloride--ethyl acetate 6-4), 11.45 g of theexpected product with a Rf=0.3 (CH₂ Cl₂ -AcOEt 9-1)

Stage H:[[1-[2-chloro-4,5bis-[(2-methoxyethoxy)-methoxy]phenyl-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-(2-[(triphenyl-methyl)-amino]-thiazol-4-yl]aceticacid

Using the procedure of Stage E of Example 1, 11.45 g of the product ofStage G and 9.03 g of oxo-[2-[(triphenylmethyl)amino]-thiazol-4-yl]-acetic acid (described in Belgian Application No. 864828) were reactedto obtain 18.77 g of the expected product with a Rf=0.3 (CH₂ Cl₂ -MeOH6-4)

Stage I:4-methoxybenzyl-7β-[[[[1-[2-chloro-4,5bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1azabicyclo[4,2,0]oct-2-en-2-carboxylate

Using the procedure of Stage F of Example 1, the product of Stage H and8.2 g of4-methoxybenzyl-7β-amino-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylatehydrochloride (EP 0,333,154 ) were reacted to obtain afterchromatography on silica, (eluant: methylene chloride--ethyl acetate(9-1)), 5.34 g of the desired product with a Rf=0.25 (CH₂ Cl₂ -AcOEt9-1)

Stage J:4-methoxybenzyl-7β-[[[[1-[2-chloro-4,5bis-[(2-methoxy-ethoxy)-methoxy]-phenyl]-2-oxo-2-(diphenylmethoxy)ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]acetamido]-3-[(Z)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate

Using the procedure of Stage G of Example 1, 1.3 g of Stage I werereacted to obtain after chromatography on silica, (eluant: methylenechloride--ethyl acetate (9-1)), 731 mg of the desired product with aRf=0.1 (CH₂ Cl₂ -AcOEt 9-1)

EXAMPLE 119 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-4,5-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]oct-2-en-3-yl)-2-propenyl)-6,7-dihydro-5H-pyrindinium

Using the procedure of Stages A and B of Example 68, 685 mg ofcyclopenta (b) pyridine were reacted to obtain 500 mg of intermediatequaternary salt, 657 mg of which was reacted with 5 ml oftrifluoroacetic acid with 10% anisole to obtain 278 mg of the expectedproduct.

NMR spectrum: DMSO 300 MHz. 2.24 (m)-3.14 (t): indane; 3.53 (dl)-3.74(dl): the CH₂ S's; 5.13 (d)-5.16 (m): H6; 5.33 (d): CH₂ --N.sup.⊕ ; 5.71(s): O--CH--CO; 5.76 (m): H7; 6.21 m): CH═CH--CH_(2;) 6.78 (s)-6.80(s)-6.92 (s): chlorophenyl and H₅ thiazole; 6.84 (d, J=16): CH═CH--CH₂ ;7.91 (dd)-8.43 (d)-8.74 (d): pyridine.

EXAMPLE 120 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]2-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-4,5-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo-[4,2,0]oct-2-en-3-yl)-2-propenyl)-isoquinolinium.

Using the procedure of Stages A and B of Example 68, 260 mg of theiodated derivative above and 108 ml of isoquinoline were reacted toobtain 84 mg of intermediate quaternary salt, which was reacted with 2ml of trifluoroacetic acid with 10% anisole to obtain 39 mg of theexpected product.

NMR spectrum: DMSO 300 MHz. 3.45 (m): the CH₂ S's; 5.14 (d, resolved):H₆ ; 5.57 (d, resolved): CH₂ --N.sup.⊕ ; 5.71 (s): O--CH--CO; 5.76 (m):H7; 6.57 (m): CH═CH--CH₂ ; 6.78 (s, resolved): H₅ thiazole; 6.92 (d):chlorophenyl; 7.10 (d, resolved): CH═CH--CH₂ ; 8.09 (t)-8.28 (t)-8.31(d)-8.38 (d)-8.67 (d)-8.74 (dd)-10.06 (sl): isoquinoline.

EXAMPLE 121 Internal salt of(6R-(3-(E)-6α,7β-[(Z)]1-(3-(7-(((2-amino-4-thiazolyl)-(carboxy-(2-chloro-4,5-dihydroxyphenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-quinolinium.

Using the procedure of Stages A and B of Example 68, 703 mg of theiodated derivative above and 288 ml of quinoline were reacted to obtain529.5 mg of intermediate quaternary salt, which were reacted with 15 mlof trifluoroacetic acid with 10% anisole to obtain 273 mg of theexpected product.

NMR spectrum: DMSO 300 MHz. 3.45 (m): the CH₂ S's; 5.12 (d, resolved):H₆ ; 5.70 (s): O--CH--CO; 5.70 (m): H₇ ; 5.70 to 5.90: CH₂ N.sup.⊕ ;6.34 (m): CH═CH--CH₂ ; 6.75 to 6.96: H₅ thiazole, chlorophenyl andCH═CH--CH₂ ; 8.06 (m)-8.25 (m)-8.34 (m)-9.34 (d)-9.56 (m): quinoline.

Preparation of example 122:diphenylmethyl-[5-cyano-3,4-bis-[2-methoxy-ethoxy)-methoxy]-thienyl-chloro-acetate.

Stage A:3,4-bis-[2-methoxy-ethoxy)-methoxy]5-cyano-2-ethoxycarbonyl-thiophene

92 g of 3,4-dihydroxy-5-cyano-2-ethoxycarbonyl-thiophene (described inJapanese Application No. J57116064) and 860 ml of methylene chloridewere mixed together under an inert gas atmosphere at 0° C. and then 153ml of diisopropylethylamine, then 102 ml of methoxyethoxymethyl chloridewere added slowly. After 45 minutes, the reaction mixture was washedwith a 0.1N solution hydrochloric acid, then with a 1M solution ofsodium bicarbonate and finally with water saturated with sodiumchloride. After drying and evaporating the solvent, 161 g of theexpected product were obtained which was used as in the following stage:

NMR spectrum (CDCl₃, 300 MHz, ppm):

1.36 (t), 4.34 (q) CO₂ Et;

3.36 (s), 3.38 (s) 2--OCH₃ ;

3.50 to 3.63 (m) (4H), 3.94 (m) (4H) O--(CH₂)₂ --O; 5.36 (s), 5.42 (s) 2##STR276##

IR Spectrum (CHCl₂)

Absorptions at 2225 cm⁻¹ (conjugated C═N); 1720 cm⁻¹ (C═O); 1554, 1490cm⁻¹ (conjugated system).

Stage B:3,4-bis-[2-methoxy-ethoxy)-methoxy]-5-cyano-2-hydroxymethyl-thiophene

A mixture of 161 g of the product of Stage A and 1 liter oftetrahydrofuran was stirred under an inert gas atmosphere and 262 g oflithium triterbutoxy alumino hydride were added at 5° C. over 5 hours.The temperature was allowed to rise and the reaction mixture was stirredfor 36 hours. The suspension was concentrated and poured into a mixtureof 1.2 liters of a saturated aqueous solution of ammonium chloride, 1.5liters of water and 0.5 liter of ethyl acetate. The mixture was stirredfor 18 hours, followed by filtering. The filtrate was washed with asaturated aqueous solution of sodium chloride, dried and the solvent wasevaporated off to obtain 108 g of the expected product which was used asis for the following stage.

Stage C: 3,4-bis-[2-methoxy-ethoxy)-methoxy]-5-cyano-2-formyl-thiophene

450 ml of methylene chloride were added to the 108 g of the alcohol ofStage B and after the reaction mixture was cooled to 5° C., then 497 gof manganese dioxide were added slowly. After total disappearance of thestarting product, filtration was carried out and the filter was rinsedwith ethyl acetate. The filtrate was concentrated to dryness and theresidue was chromatographed on silica, eluting with methylene chlorideethyl acetate mixtures 98/2, 97/3, 96/4 to obtain 67 g of expectedproduct.

NMR spectrum (CDCl₃, 300 MHz, ppm):

3.35 (s) (3H), 3.38 (s) (3H) the O--CH₃ 's;

3.58 (m) (4H), 3.93 (m) (4H) the O--(CH₂)₂ --O's;

5.37 (s)(2H), 5.44 (s) (2H) the O--CH₂ --O's;

10.04 (s) (1H) CHO

IR Spectrum (CHCl₃)

Absorptions at 2220 cm⁻¹ (C═N); 1670 cm⁻¹ (C═O, conjugated

aldehyde); 1582, 1550, 1485 cm⁻¹ (heterocycle)

Stage D:diphenylmethyl-[5-cyano-3,4-bis[(2-methoxyethoxy)-methoxy]-thienyl-chloroacetate

63.6 g of the product of stage c, 1 liter of toluene, 15.8 g ofmalodinitrile and a 4 A molecular sieve 1.8 ml of piperidine were added.The mixture was stirred for 40 minutes and 74 ml ofterbutylhydroperoxide in a 3M solution in toluene were added to thereaction mixture over 5 minutes without exceeding 11° C. After 20minutes, the mixture was filtered, the filter was rinsed with ethylacetate and the solvent was evaporated to obtain 82 g of an oil of adicyanoepoxide. The product was taken up in 1.8 liters oftetranhydrofuran and 240 ml of 1N hydrochloric acid were added to thesolution over about 7 minutes followed by stirring at ambienttemperature for 1 hour.

870 ml of a solution of 0.38 mol/l of diphenyldiazomethane in ethylether were added to the reaction mixture over about 12 minutes which wasthen stirred for 2 hours at ambient temperature. Extraction with ethylether was followed by washing with 1N sodium hydroxide then with watersaturated with sodium chloride. The organic phase was dried and thesolvent was evaporated. The residue was chromatographed on silicaeluting with cyclohexane--ethyl acetate mixtures (4/1), (3/1) then (2/1)to obtain 68 g of the expected product.

NMR spectrum (CDCl₃, 250 MHz, ppm):

3.31 (s) (3H), 3.36 (s) (3H) the O--CH₃ 's;

3.48 (m), 3.58 (m), 3.82 (m),

3.92 (m) (8H) the O--(CH₂)₂ --O's;

5.17 (syst. AB), 5.41 (s) (2H) the O--CH₂ --O's;

5.98 (s) (1H) ##STR277## 6.91 (s) (1H) CO₂ --CH--Φ₂ ; 7.34 (m) (10H) thephenyls.

IR Spectrum (CHCl₃)

Absorptions at 2221 cm⁻¹ (C═N); 1746 cm⁻¹ (C═O), 1603, 1589, 1496 cm⁻¹(aromatic-heteroatom)

EXAMPLE 122 Internal salt of(6R-[(3-(E)-6α,7β-[(Z)]]-1-[3-[7-[[2-amino-4-thiazolyl)-[carboxy-5-cyano-3,4-dihydroxy-2-thienyl)-methoxy]-imino]-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-quinolinium.

Stage A: diphenylmethyl-[5-cyano-3,4bis-[(2-methoxyethoxy)-methoxy]-thienyl]-phthalimidoxy-acetate

13.1 g of N-hydroxy phthalimide, 6.55g of sodium bicarbonate and 400 mlof water were mixed together and after the mixture was stirred for 2hours, 25 g of diphenylmethyl[5-cyano-3,4bis-[(2-methoxy-ethoxy)-methoxy]-thienyl-chloroacetate in400 ml of dichlorethane were added. 0.89 g of triethyl benzylammoniumchloride were added and the mixture was stirred for 13 hours at ambienttemperature, followed by extraction with dichlorethane. The organicphase was washed with water with sodium chloride added to it, dried andthe solvent was evaporated. The residue was purified by chromatographyon silica eluting with a cyclohexane--ethyl acetate mixture (6-4), then(1-1) to obtain 15.4 g of the expected product.

NMR spectrum (CDCl₃, 300 MHz, ppm):

3.28 (s)(3H), 3.36 (s)(3H) --O--CH₃ ;

3.46 (m) (2H), 3.58 (m) (2H),

3.78 to 3.95 (m) (4H) --O--(CH₂)₂ --O;

5.21 (AB) (2H), 5.37 (AB) (2H) O--CH₂ --O;

6.26(s) (1H) ##STR278## 6.96 (s) (1H) --CO₂ --CH--Φ₂ ; 7.2 to 7.4 (m)(10H), 7.75 (m) (4H) phthalimide H.

IR Spectrum (CHCl₃)

Absorptions at 2222 cm⁻¹ : --C═N; 1796 and 1740 cm⁻¹ C═O,

1610-1580 cm⁻¹ and 1496 cm⁻¹ : conjugated system+aromatic.

Stage B: diphenylmethylaminoxy-[5-cyano-3,4bis-[(2-methoxyethoxy)-methoxy]-thienyl]-acetate

5.06 g of the product of Stage A were dissolved under a nitrogenatmosphere in 72 ml of methanol and the mixture was cooled to -11° C.Then, 0.35 ml of hydrazine hydrate were added and the same temperatureis maintained for 15 minutes after which, another 0.02 ml of hydrazinehydrate were added. After 30 minutes, another 0.04 ml were added to thereaction mixture and stirred for 45 minutes to obtain the expectedproduct in solution, which is used as is for the following stage.

Stage C:[[[2-[5-cyano-3,4-bis-[(2-methoxy-ethoxy)-methoxy]-thienyl]-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2triphenylmethyl)-amino]-thiazol-4-yl]-aceticacid

3 g of oxo-[2-triphenylmethyl)-amino]-thiazol-4-yl]-acetic acid(described in Belgian Patent Application No. 864828) were added to thesolution of Stage B and the temperature was allowed to rise. 10 ml ofmethylene chloride were added then the crystals formed were separated.The filtrate was concentrated to dryness and the residue waschromatographed on silica eluting with methylene chlorride--methanolmixture (95-5) to obtain a total of 5.5 g of the crude expected product.

Stage D:4-methoxybenzyl-7β-[[[[[2-[5-cyano-3,4bis-[2-methoxy-ethoxy)-methoxy]-thienyl]-2-oxo-2-(diphenylmethoxy)-ethyl]oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-3-[(Z)-3-chloro-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate

2.44 g of4-methoxybenzyl-7β-amino-3-[(Z)-3-chloro-1propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylatehydrochloride (described in European Patent Application No. 0,333,154),5.5 g of the product of Stage C and 60 ml of methylene chloride weremixed together at 0° C. and then, 1.75 g of1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide (EDC) were added. Themixture was stirred for 45 minutes while allowing the temperature torise. The reaction medium was treated with 100 ml of 0.5 M potassiumhydrogenophosphate and then washed with a sodium chloride solution.After drying, the solvent was evaporated to obtain 8.5 g of the expectedproduct with a Rf=0.42 [eluant: methylene chloride--ethyl acetate(9-1)]which can be purified by chromatography on silica eluting with acyclohexane--ethyl acetate mixture (1-1)

NMR. spectrum (CDCl₃, 300 MHz, ppm):

3.20 3.34 --O--CH₃, S--CH₂ --;

3.43 (m), 3.59 (m), 3.92 (m),

3.45 3.90, 4.14 (m) (1H) --O--CH₂ --CH₂ --O, --CH--CH₂ --X

5.02 (m) H₆ ;

5.86 (m), H₇ ;

5.40 to 5.50 o--CH--OCO, O--CH₂ --O;

5.78 (m) CH₂ --CH═CH--(ΔZ);

6.20 to 6.35 CH₂ --CH═CH--(ΔZ);

6.77 (s/d) H₅ thiazole;

6.91 (m) (4H) Aromatics, --CO₂ --CH--Φ, NH--CO--

IR Spectrum (CHCl₃) Absorptions at 3404 cm⁻¹ : ═C--NH--; 2221 cm⁻¹ :--C═N; 1791, and 1684 cm⁻¹ : β-lactame; 1613, 1587, 1526, 1517 and 1496cm⁻¹ : aromatic C═C, heteroatom and amide II.

Stage E:4-methoxybenzyl-7β-[[[[[2-[5-Cyano-3,4bis-[2-methoxy-ethoxy)-methoxy]-thienyl]-2-oxo-2-(diphenylmethoxy)ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]acetamido]-3-[(Z)-3-iodo-1-propenyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate

1.5 g of the product after chromatography in Stage D, 20 ml of acetoneand 0.5 g of Sodium iodide were stirred for 70 minutes at ambienttemperature in the presence of 30 mg of iodine. After elimination of thesolvent, the residue was taken up in methylene chloride and the organicphase was washed with a sodium thiosulfate solution then with a sodiumchloride solution and dried. The solvent was eliminated and the residuewas chromatographed on silica eluting with a cyclohexane--ethyl acetatemixture (1-1) to obtain 0.9 g of the expected iodated product.

Stage F:1-[3-[7β-[[[[[2-[5-cyano-3,4-bis-[(2-methoxyethoxy)-methoxy]-thienyl]-2-2-oxo-2-(diphenylmethoxy)-ethyl]-oxy]-imino]-[2-(triphenylmethyl)-amino]-thiazol-4-yl]-acetamido]-2-[(4methoxybenzyloxy)-carbonyl]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinoliniumiodide

0.450 g of the product of Stage E were dissolved in 5 ml of methylenechloride and 185 μl of quinoline were added with stirring and thesolvent was evaporated. The mixture was stirred for 80 minutes, followedby taking up in ether, crystallizing, separating and chromatographing onsilica eluting with a methylene chloride methanol mixture (95-5) toobtain 0.260 g of the expected product with a Rf=0,37 [eluant: methylenechloride--methanol (90-10)].

Stage G: Internal salt of[6R-[3-(E)-6α,7β-(Z)]]-1-[3-[7-[[2-amino-4-thiazolyl)-[carboxy-(5-cyano-3,4-dihyroxy-2-thienyl)methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium

A mixture of 0.255 g of the product of Stage F and 3 ml oftrifluoroacetic acid containg 10% anisole was stirred at ambienttemperature for 2 hours and 45 minutes. After adding isopropyl ether,filtering, washing and drying for 16 hours under reduced pressure atambient temperature, 0.118 g of the desired internal salt were isolated.

NMR analysis of the proton (DMSO 300 MHz in ppm)

R/S structure; Δ3 syn; ΔE/ΔZ mixture ˜70/30.

5.18 (m) and 5.30 (m) (1H): H6;

5.65/5.90 (<4H): H₇, ##STR279## ═CH--CH₂ --N⁺ and ═CH--CH₂ (ΔZ) 6.39 (m)(0.7H): C═CH--H₂ (E);

6.61 (d, J=11) (0.3H): C═CH--CH₂ (Z) ;

6.70 (s) and 6.74 (s) (1H): H₅ thiazole;

6.95 (d, J=15.5): ═C--CH--CH (ΔE);

8.07 (m) (1H), 8.29 (m) (2H), 8.51 (m) (2H), 9.34 (m) (1H)

and 9.57 (m) (1H): H of the quinolinium;

11.6 (1 ): ═C--NH--CH.

IR Spectrum (nujol)

General absorption OH/NH, 2215 cm⁻¹ : Conjugated C═N, 1778 cm⁻¹,β-lactame, 1672 cm⁻¹ : other C═O

Preparation of example 123diphenylmethyl-α-bromo-[5-(terbutoxy-carbonyl)-amino]-3-(1,2,4-thiadiazole)-acetate

Stage A:diphenylmethyl-[5-(terbutoxy-carbonyl)-amino]-3-(1,2,4-thiadiazole)-acetate

7.25 g of [5-(terbutoxycarbonyl)-amino-3-(1,2,4-thiadiazole acetic acidwere mixed at ambient temperature with 90 ml of methylene chloride and49 ml of methanol. The solution was cooled to 0° C. and 93.3 ml ofdiphenyl-diazomethane in a 0.3M solution in ether were added dropwise.The reaction medium was allowed to return to ambient temperature over 2hours 30 minutes and the solvents were evaporated under reduced pressureto obtain i3.66 g of crude product which was chromatographed on silica(eluant: methylene chloride-acetonitrile 98-2) to obtain 8.38 g of theexpected product.

NMR Spectrum (CDCl₃ 300 MHz in ppm)

1,52 (s) terbutyl

4,06 (s) CH₂ --CO₂

6,92 CH₂ --CH--Φ₂

7,26 (s) phenyls

10,20 (sl) NH

Stage B:diphenylmethyl-α-bromo-[5-(terbutoxycarbonyl)amino]-3-(1,2,4-thiadiazole)-acetate

146 mg of bromine (47 μl) were added to 390 mg of the ester of Stage Ain solution in 6 ml of acetic acid and the mixture was stirred for 2hours 30 minutes at ambient temperature. The solvent was evaporated andthe residue was taken up in methylene chloride, washed with an aqueoussolution of sodium bicarbonate at 10%, dried and the solvents wereevaporated to obtain 390 mg of the crude product which waschromatographed on silica (eluant: methylene chloride) to obtain 190 mgof the expected product.

NMR Spectrum (CDCl₃ 250 MHz in ppm)

1,55 terbutyl

6,95 phenyls

7,2 to 7,4--CH--Br

9,23 NH

EXAMPLE 123 Internal salt of(6R-[(3-(E)-6α,7β-[(Z)]]-1-[3-[7-[[2-amino-4-thiazolyl)-[carboxy-(5-amino-1,2,4-thiadiazol-3-yl)-methoxy]-imino]-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl]-quinolinium

Stage A:diphenylmethyl-α-phthalimidoxy-[5-(terbutoxycarbonyl)-amino]-3-(1,2,4-thiadiazole)-acetate

130 mg of sodium bicarbonate and 252 mg of hydroxy-phthalimide in 3 mlof water were stirred for one hour under an inert atmosphere and then390 mg of the bromo ester of Preparation above then 17.6 mg oftriethylbenzylammonium chloride were added dropwise. Vigorous stirringwas carried out for 20 hours. 10 to 20 ml of methylene chloride wereadded, followed by decanting, extracting with methylene chloride, dryingand evaporating the solvent to obtain 426 mg of crude product. Thelatter was purified by chromatography on silica (eluant: methylenechloride--ethyl acetate 98-2) to obtain 169 mg of the expected product.

NMR Spectrum (CDCl₃ 300 MHz in ppm)

1,56 (s) terbutyl

5,98 (s) --CH--COO

7,07 (S) CH--Φ₂

7,15 to 7,35 phenyl

7,72 (m)-7,76 (m) phthalimide

8,53 (sl) --NH--

Stage B:diphenytmethyl-α-aminoxy-[5-terbutoxycarbonyl)amino]-3-(1,2,4-thiadiazole)-acetate

58 mg of the phthalimido ester of Stage A in i ml of methylene chloridewere cooled to 0° C. under an inert atmosphere and then 5.5 μl ofhydrazine hydrate were added. The mixture was stirred for 30 minutes,followed by filtration. The precipitate was rinsed with methylenechloride and the solvent was evaporated under reduced pressure atambient temperature to obtain 58 mg of crude product which waschromatographed on silica (eluant: cyclohexane--ethyl acetate 7-3) toobtain 26 mg of the expected product.

NMR Spectrum (CDCl₃ 300 MHz in ppm)

1,55 (sl) terbutyl

6,22 (s) --CH--COO

6,90 to 7,30 phenyls

6,96 or 7,10 O--CH--Φ

3,10 mobile H's

Stage C:1-[3-[7-[[2-(triphenylmethyl)-amino]-4-thiazolyl-(2-diphenylmethoxy)-carbonyl]-[5-(terbutoxycarbonyl)-amino]-(1,2,4-thiadiazol-3-yl)-methoxy]-imino]-acetamido]-2-[(4-methoxy)-benzyloxycarbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]oct-2-en-3-yl]-2-propenyl]quinoliniumiodide

65.4 mg of1-[3-[7β-[oxo-[2-(triphenylmethyl)-amino]-4thiazolyl]-acetamido]-2-[(4-methoxy)-benzyloxycarbonyl]-8-oxo-5-thia-1-azabicyclo-[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinoliniumiodide, 1 ml of methanol and 0.3 ml of methylene chloride were mixedtogether under an inert atmosphere chloride were mixed together under aninert atmosphere at ambient temperature and 36 mg of the aminoxyderivative of Stage B in 0.5 ml of methylene chloride were added. Then12.5 mg of toluene sulfonic acid were added and the mixture was stirredfor 20 hours at ambient temperature. The solvent was evaporated underreduced pressure at ambient temperature and the residue was taken up inether. After stirring for 15 minutes, the precipitate was filtered anddried under reduced pressure for one hour to obtain 83 mg of crudeproduct which was used as is for the rest of the synthesis.

Stage D: Internal salt of(6R-[(3-(E)-6α,7β-[(Z)]]-1-[3-[7[[(2-amino-4-thiazolyl)-[carboxy-(5-amino-1,2,4-thiadiazol-3-yl]-methoxy]-imino]-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium

83 mg of the crude product of Stage C in 0.8 ml of a solution oftrifluoroacetic acid with 10% anisole were stirred for 3 hours atambient temperature. Filtration was carried out, followed by rinsingwith trifluoroacetic acid. Then, about 2 ml of ethyl ether were addedand the mixture was stirred for 30 minutes. After filtering and rinsingwith ether, the precipitate was dried under reduced pressure for 16hours at ambient temperature to obtain 34 mg of the expected crudeproduct.

NMR Spectrum (CDCl₃ 300 MHz in ppm)

5,26 (d) H₆

5,48 (d,d) after exchange 6,53 (d) H₇

6,09 (dt) ΔE CH═CH--CH₂

6,53 CH═CH--CH₂

6.75 (s) H₅ of the thiazole

9,73 (d, mobile) --NH--

In addition to the products described above in the Examples, thefollowing products constitute products which can be obtained by themethods of the invention:

    __________________________________________________________________________    R.sub.7   R.sub.6  R.sub.7   R.sub.6                                          __________________________________________________________________________     ##STR280##                                                                              ##STR281##                                                                             ##STR282##                                                                              ##STR283##                                                 ##STR284##                                                                            "                                                                                        ##STR285##                                      "                                                                                        ##STR286##                                                                            "                                                                                        ##STR287##                                      "                                                                                        ##STR288##                                                                            "                                                                                        ##STR289##                                      "                                                                                        ##STR290##                                                                            "                                                                                        ##STR291##                                      "                                                                                        ##STR292##                                                                            "                                                                                        ##STR293##                                                         "                                                                                        ##STR294##                                                         "                                                                                        ##STR295##                                                         "                                                                                        ##STR296##                                       ##STR297##                                                                              ##STR298##                                                                             ##STR299##                                                                              ##STR300##                                      "                                                                                        ##STR301##                                                                            "                                                                                        ##STR302##                                      "                                                                                        ##STR303##                                                                            "                                                                                        ##STR304##                                      "                                                                                        ##STR305##                                                                            "                                                                                        ##STR306##                                      "                                                                                        ##STR307##                                                                            "                                                                                        ##STR308##                                      "                                                                                        ##STR309##                                                                            "                                                                                        ##STR310##                                      "                                                                                        ##STR311##                                                                            "                                                                                        ##STR312##                                      "                                                                                        ##STR313##                                                         "                                                                                        ##STR314##                                                         __________________________________________________________________________

EXAMPLE 124 The following preparations for injections were made:

containing 500 mg of the product of Example 2 or 121

and sufficient sterile aqueous excipient for 5 ml

PHARMACOLOGICAL STUDY

In vitro activity, method of dilutions in liquid medium.

A series of tubes was prepared in which an equal amount of sterilenutritional medium was distributed and increasing amounts of the testproduct was distributed into each tube. Then, each tube was seeded witha bacterial strain and after incubation in an oven for twenty four hoursat 37° C. The growth inhibition was evaluated by transillumination whichallowed the minimal inhibiting concentrations (M.I.C.) to be determined,expressed in ug/ml (TABLE I).

In vitro activity, method of dilutions in solid medium.

A series of dishes was prepared in which an equal amount of sterilenutritional medium was distributed containing increasing amounts of thetest product. Then, each dish was seeded with several bacteria strainsand after incubation in an oven for 24 hours at 37° C., the growthinhibition was evaluated by the absence of any bacterial development,which allowed the minimal inhibiting concentrations (M.I.C.) to bedetermined expressed in micrograms/mi. The results were expressed inM.I.C.₉₀ which is the minimum concentration of antibiotic allowing thegrowth of the strains studied to be inhibited by 90° (TABLE II)

                                      TABLE II                                    __________________________________________________________________________    MIC.sub.90                                                                          oracillin-sensitive                                                                    Enterobacteria                                                                        Enterobacteria                                               penicillin-resis-                                                                      producing                                                                             producing                                                    tants Staphylococci                                                                    cephalospori-                                                                         β lactamase with                                                                  Pseudomona                                    Product of                                                                          aureus   nases   enlarged spectrum                                                                      Aeuginosa                                     example                                                                             (20 strains)                                                                           (20 strains)                                                                          (16 strains)                                                                           (39 strains)                                  __________________________________________________________________________    39    2,5      0,3     2,5      0,08                                          43    0,3      2,5     1,2      1,2                                           -27   5        0,3     10       0,08                                          __________________________________________________________________________

Activity in vitro, method of dilutions in solid medium.

A series of dishes were prepared in which an equal quantity of sterilenutritive medium was distributed containing increasing quantities of theproduct to be studied and then each dish was seeded with severalbacterial strain. After incubation for 24 hours in an oven at 37° C.,the growth inhibition was evaluated by the absence of any bacterialdevelopment which allowed the minimum inhibiting concentrations (MIC)expressed in micrograms/cm³ to be determined. The results are expressedin MIC₅₀ and MIC₉₀ which is the minimum concentration of antibioticinhibiting the growth of the strains studied by 50 and 90%. Thefollowing results were obtained:

    ______________________________________                                                      < >      MIC.sub.50                                                                            MIC.sub.90                                     ______________________________________                                        Strains                                                                       Penicillin-      0.04-0.15 0.15    0.15                                       sensitive Staphylococcus                                                      aureus (14 strains)                                                           Penicillin-     0.08-1.2   0.15    0.15                                       resistant staphylococcus                                                      aureus (21 strains)                                                           Streptococci group D                                                                          2.5-20     2.5     5                                          (10 strains)                                                                  Enterobacteria                                                                producing                                                                     β-lactamases                                                             Chromosomal     0.15-5     1.2     5                                          Plasmidic                                                                     SHV-2 (13 strains)                                                                            0.08-1.2   0.3     1.2                                        SHV-4 (29 strains)                                                                            0.6-20     2.5     5                                          TEM-3 (35 strains)                                                                            0.15-20    1.2     2.5                                        ______________________________________                                    

Various modifications of the products and methods of the invention maybe made without departing from the spirit or scope thereof. It is to beunderstood that the invention is intended to be limited only as definedin the appended claims.

What we claim is:
 1. A syn isomer in (R) or (S) form or a mixturethereof of a compound of the formula ##STR315## syn isomer, in the (R)or (S) form or in the form of an (R,S) mixture, in the form of aninternal salt or their salts with organic or mineral acids wherein R₇ isselected from the group consisting of ##STR316## R'₁ is selected fromthe group consisting of alkyl of 1 to 4 carbon atoms, --CN, carboxy andalkoxy carbonyl of 1 to 4 alkoxy carbon atoms, R₁, R₂, R₃ and R₅ areindividually selected from the group consisting of hydrogen, halogen,hydroxy, alkyl of 1 to 4 carbon atoms optionally substituted with atleast one member of the group consisting of halogen, alkoxy andalkylthio of 1 to 4 carbon atoms, --NO₂, --CN, --NH₂, mono- anddialkylamino of 1 to 4 carbon atoms, carbamoyl, (alkylamino) carbonyl of2 to 5 carbon atoms, (dialkylamino) carbonyl of 3 to 9 carbon atoms,carboxy, alkoxycarbonyl of 2 to 5 carbon atoms, acyloxy of 1 to 8 carbonatoms and ##STR317## and Ry are individually hydrogen or alkyl of 1 to 4carbon atoms, R₄ is --OH or alkoxy of 1 to 8 carbon atoms, A and A' areindividually selected from the group consisting of hydrogen, anequivalent of an alkali metal or alkaline earth metal, magnesiumammonium and an organic amine, or one or two of --COOA or --COOA' are--CO₂, the wavy line means --CH₂ R₆ can be in the E or Z position, R₆ inthe quaternary ammonium form is selected from the group consisting of##STR318## X is selected from the group consisting of --CH₂, --NH--,--O-- and --S--, Q, J, Y, T, U, V, W and Z are individually ═N-- or--CH═, each of cyclics containing 1 to 5 heteroatoms selected from thegroup consisting of oxygen, sulfur and nitrogen of which at least one is═N-- and optionally substituted by at least one R or R', R and R' areindividually selected from the group consisting of halogen, alkyl andalkoxy of 1 to 4 carbon atoms, halogen, --CN, --COOQ₁, --CONQ₁ Q₂, --NQ₁Q₂, --SO₂ NQ₁ Q₂, --CSNH₂, --NHCOQ₁, --CH═NOH, --CH═N--O--Q₁, --CH₂ CH,--SQ₁, and --CH₂ --S--Q₁, Q₁ and Q₂ are individually hydrogen or alkylof 1 to 4 carbon atoms, with the proviso that when R₃ is --OH or alkoxyof 1 to 8 carbon atoms, at least one of R₁, R₂ and R₅ is other thanhydrogen.
 2. A compound of claim 1 wherein R₆ is selected from the groupconsisting of ##STR319##
 3. A compound of claim 1 wherein R₃ and R₄ are--OH.
 4. A compound of claim 1 wherein R₂ and R₅ are chlorine.
 5. Acompound of claim 1 wherein R₂ and R₅ are fluorine.
 6. A compound ofclaim 1 wherein R₁ and R₂ are fluorine.
 7. A compound of claim 1 whereinR₂ is --OCH₃ and one of R₁ or R₅ is chlorine.
 8. A compound of claim 1wherein R₆ is selected from the group consisting of quinolinium,isoquinolinium, thieno[2,3-b]pyridinium, imidazo (1,2-a) pyridinium and6,7-dihydro-5H-pyridinium.
 9. A compound of claim 1 selected from thegroup consisting ofthe internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)imidazo (1,2-a) pyridinium, the internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-imidazo(1,2-a) pyridinium, the internal salt of (6R-(3-(E)6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2-chloro-4,5-dihydroxy-3-methoxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl) quinolinium, the internal salt of(6R-3-(E) 6α,7β(Z)))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-6,7-dihydro-5H-pyrindinium, theinternal salt of (6R-(3-(E)6α,7β(Z(S*))))-1-(3-(7-(((2-amino-4-thiazolyl)(carboxy-(3,4-dihydroxy-5-fluorophenyl)-methoxy)-imino)-acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-quinolinium, the internal salt of[6R-[3(E) 6α,7β(Z)]]1-[3-[7-[[2-amino-4-thiazolyl)[carboxy-(2-chloro-3,4-dihydroxy-phenyl)-methoxy]imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium (R) or (S) or an (R+S)mixture, the internal salt of [6R-[3(E)6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)[carboxy-(3-cyano-4,5-dihydroxy-phenyl)-methoxy]imino]acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]quinolinium(R) or (S) or an (R+S) mixture, the internal salt of [6R-[3(E)6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)[carboxy-(3-fluoro-4,5-dihydroxy-phenyl)-methoxy]imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium(R) or (S) or an (R+S) mixture the internal salt of [6R-[3(E)6α,7β(Z)]]-1-[3-[7-[[2-amino-4-thiazolyl)[carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxyimino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl-2-propenyl]-thieno[2,3-b]pyridinium (R) or (S) or an (R+S) mixture, the internal salt of[6R-[3(E) 6α,7β(Z)]]-1-[3-[7-[[2-amino-4-thiazolyl)[carboxy-(2,5-dichloro-3,4-dihydroxy-pheny)-methoxy]imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium (R) or (S) or an (R+S)mixture, the internal salt of [6R-[3(E)6α,7β[Z(S*)]]]-1-[3-[7-[[(2-amino-4-thiazolyl)[carboxy-(3-cyano-4,5-dihydroxy-phenyl)-methoxy]imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-thieno [2,3-b]pyridinium, the internalsalt of [6R-[3(E) 6α,7β(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)[carboxy-(2,5-dichloro-3,4-dihydroxy-phenyl)-methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-isoquinolinium (R) or (S) or an (R+S)mixture and the internal salt of[6R-[3-(E)-6α,7β-[(Z(S*)]]-1-[3-7-[[(2-amino-4-thiazolyl)-[carboxy-(2,3-difluoro-4,5-dihydroxy-phenyl)methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinoliniumthe internal salt of[6R-[3-(E)-6α,7β-[Z(S*)]]-1-[3-7-[[(2-amino-4-thiazolyl)-[carboxy-(2,5-difluoro-3,4-dihydroxy-phenyl)methoxy]-imino]-acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-propenyl]-quinolinium.10. A compound of claim 1 having the formula ##STR320## wherein R₇ is##STR321## in which R'₁ is alkyl of 1 to 4 carbon atoms, cyano, carboxyor alkoxy-carbonyl of 1 to 4 alkoxy carbon atoms, or R₇ is ##STR322## Aand A' are individually hydrogen, an equivalent of an alkali metal,alkaline-earth metal, magnesium, ammonium or an organic amino base, orone only or each of the CO₂ A or CO₂ A' groups is CO₂, the wavy lineindicates that --CH₂ R₆ can be found in the E or Z position and R₆ is inthe quaternary ammonium form selected from the group consisting of##STR323## in which X is --CH₂, --NH, --O or S; R, R', Q, J, Y, T, U, V,W and Z are defined as in claim
 1. 11. A compound of claim 10 in whichR₆ is selected from the group consisting of ##STR324##
 12. A compound ofclaim 1 in which R'₁ is cyano, carboxy or alkoxycarbonyl.
 13. A compoundof claim 10 which is the internal salt of [6R-[3-(E)6α,7β-(Z)]]-1-[3-[7-[[(2-amino-4-thiazolyl)-[[carboxy-5-cyano-3,4-dihydroxy-2-thieny)-methoxy]-imino]-acetyl]-amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-propenyl)-quinolinium.14. An antibacterial composition comprising an antibactericidallyeffective amount of at least one compound of claim 1 and an inertpharmaceutical carrier.
 15. A method of treating bacterial infections inwarm-blooded animals comprising administering to warm-blooded animals anantibacterically effective amount of at least one compound of claim 1.16. A method of treating bacterial infections in warm-blooded animalscomprising administering to warm-blooded animals an antibacteriallyeffective amount of at least one compound of claim
 2. 17. A method oftreating bacterial infections in warm-blooded animals comprisingadministering to warm-blooded animals an antibacterially effectiveamount of at least one compound of claim
 9. 18. A method of treatingbacterial infections in warm-blooded animals comprising administering towarm-blooded animals an antibacterially effective amount of at least onecompound of claim
 13. 19. A compound of claim 10 wherein R₆ is selectedfrom the group consisting of quinolinium, isoquinolinium,thieno[2,3-b]pyridinium, imidazo (1,2-a) pyridinium and6,7-dihydro-5H-pyridinium.